TWI312682B - Heteroaromatic quinoline compounds and pharmaceutical compositions comprising the same - Google Patents

Description

1312682 IX. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to heteroaromatic compounds which are useful as phosphodiesterase (PDE) inhibitors. The present invention also relates to compounds which are selective inhibitors of 1 > 1). The invention further relates to intermediates useful in the preparation of such compounds, pharmaceutical compositions comprising such compounds; and the use of such compounds in methods for treating a particular central nervous system (CNS) or other disease. The present invention also relates to methods useful for treating neurodegenerative diseases and psychiatric diseases such as psychosis and diseases including cognitive deficits as a symptom. [Prior Art] Phosphodiacetate (PDEs) are a group of intracellular enzymes involved in the hydrolysis of nucleotide adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMp) to form And other individual nucleotides. The cyclic nucleotides cAMp and cGMP can be synthesized using adenylate cyclase and guanylate cyclase, respectively, and serve as secondary messengers in several cell pathways. — The functions of CAMP and cGMP can be used as secondary messengers within the cell to regulate a large number of intracellular procedures, especially in the neurons of the central nervous system. In neurons, this function includes activation of eAMp and dependent kinases and subsequent protein sclerotation, and involves regulation of synaptic transmission as well as neuronal differentiation and survival. The complexity of cyclic nucleotide signaling can be related to cAMP and The molecular diversity of the enzymes for cGMP synthesis and decomposition shows that it contains at least ten groups of adenine cyclase, two groups of oxalate cyclase, and a ten-group phosphodiesterase. Furthermore, different types of neurons are known to exhibit multiplex isomerases in each of these groups and have a good 106557.doc 1312682 4 is not available for use in a given neuron. Separation and functional specificity of the enzyme. The primary mechanism that can be used to modulate cyclic nucleotide signaling is to utilize % nucleotide dissociation of the catalyzed phosphodiazepamase. There are currently several known pDEs, which are encoded by 21 different genes. Each gene typically produces multiple cuts that can be further advanced into isomerase diversity. The pde population can be functionally differentiated based on the specificity of the cyclic nucleotide, the regulatory machinery, and the sensitivity of the inhibitor. Furthermore, PDEs can be expressed separately through organisms, including in the central nervous system. Due to the activity and maturation of these different enzymes, different pDE isomerases have different physiological functions. Furthermore, such compounds that selectively inhibit different PDE populations or isomerases may provide particular therapeutic effects, fewer side effects, or both. PDE 10 has been identified as a single population based on major amino acid sequences and different enzyme activities. The homologous screening of the EST database revealed that mouse PDE10A could be the first member of the PDE10 population of PDE (Fujishige et al., J. Biol. Chem. 274: 18438-18445, 1999; Loughney, K. et Al·, Gene 234. 109-117, 1999). Murine homologs have also been cloned (Soderling, S. et al., proc. Natl. Acad. Sci. USA 96: 7071-7076, 1999) and N-terminal cleavage of both mice or humans The mutant strain has been identified (Kotera, J. et al., Biochem. Biophys. Res. Comm. 261: 551-557, 1999; Fujishige, K. et al., Eur. J. Biochem. 266: 1118-1127, 1999). High homology between different species. Mouse PDE 10A1 is a protein containing 779 amino acids which can be hydrolyzed to AMP and GMP by cAMP and cGMP, respectively. PDE10 has an affinity for 106557.doc 1312682 cAMP (Km=(K05 μΜ) is higher than its affinity for cgmp (Km=3 μΜ). However, since its Vmax for cGmp is five times higher than CAMP', It has been suggested that the PDE10 is a unique cAMP-inhibiting cGMP enzyme (Fujishige et al, j. Bi〇l. Chem. 274: 18438-18445, 1999).

The PDE l〇 group of the multi-peptide and the previously identified Pde group show a low degree of homology and have been shown to be insensitive to specific inhibitors. The lines are known to be specific to other PDE populations. . U.S. Patent No. 6,350,603 is incorporated herein by reference. PDE10 is also uniquely localized in mammals compared to other PDE populations. The mRNA that can be used for PDE10 will only be highly expressed in the testicles and brain.

Come out (Fujishige, K. et al., Eur J Biochem. 266: 1118-1127, 1999; Soderling, S. et al., Proc. Natl. Acad. Sci. 96: 7071-7076, 1999; Loughney, K. Et al., Gene 234: 109-117, 1999). These initial studies showed that PDE10 was most expressed in the striatum (tail appendages and dura mater), n. accumbens, and olfactory tubercle. Recently, detailed analysis of the expression pattern of PDE10 mRNA in the brain of caries (Seeger, TF et al., Abst_Soc. Neurosci. 26: 345.10, 2000) and the expression pattern of PDE10 protein (Menniti, FS, Stick, CA). Seeger, TF, and Ryan, AM, Immunohistochemical localization of PDE10 in the rat brain. William Harvey Research Conference 'Phosphodiesterase in Health and Disease', Porto, Portugal, Dec. 5-7, 2001) ° Multiple treatments for PDE inhibitors Uses The study included mandatory lungs 106557.doc 1312682 disease, allergies, hypertension, angina pectoris, congestive heart failure, depression and erectile dysfunction (W0 01/41807 A2, which is incorporated herein by reference) The use of selected benzimidazoles and related heterocyclic compounds in the treatment of ischemic heart disease has been disclosed to be based on the inhibition of PDE-related CGMP activity. U.S. Patent No. 5,693,652 is incorporated herein by reference. Patent Application Publication No. 2003/0032579 discloses a method that can be used to treat specific neurological and psychiatric disorders, a selective pDEi inhibitor, papaverine. In particular, the method relates to psychiatric disorders such as schizophrenia, delusional and drug-induced psychosis, to depression, such as panic disorder and obsessive-compulsive disorder; Including Parkinson's disease and Huntington's disease. SUMMARY OF THE INVENTION The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

Where Z is 106557.doc 1312682

Each of R1 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, fluorene to oxime, I to C8 alkenyl 'C2 to C8 alkynyl, (^ to alkoxy, to hydrazino, C3 to Cs cycloalkyl, C3 to Cs cycloalkyl-(^ to 匚8 alkyl, 4 to 7 membered heterocyclic, CjC8^thio, -NR3R3, -0-CF3, -S(0)n-R3 And c(〇)_NR3R3 and a group substituted by a hetero atom (: 丨 to ^ alkyl, wherein the hetero atom is selected from the group consisting of nitrogen, oxygen and sulfur, wherein the hetero atom may be further substituted by one a substituent selected from the group consisting of hydrogen, (^ to ^alkyl, ^ to anthracenyl, C2 to cs alkenyl, C2 to C8 alkynyl, and (^ to (: 8 haloalkyl); each The R3 series are respectively selected from the group consisting of hydrogen, (^ to (8 alkyl, (2: to 8: alkenyl, (2: 2 to C8), (^ to 匕 haloalkyl, C3 to C8 cycloalkyl) a group; R2 is selected from the group consisting of hydrogen, (^ to (8 alkyl, C3 to C8 cycloalkyl-(^ to. alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, c^cs halane) a group consisting of a c-c8 cycloalkyl group; the HET is selected from the group consisting of a monocyclic heteroaryl group and a bicyclic heteroaryl group, wherein a monocyclic ring and a heterocyclic heteroaryl group may be required Substituted by at least one R4, and R4 is selected from the group consisting of halogen, hydroxy, cyano, decyl, decyl, alkenyl, C2 to C8 alkynyl, (^ to decyloxy, C3 to C8 ring Alkyl, (: 3 to (8-cycloalkyl-(^-)-alkyl, CilCg alkylthio and substituted with a substituent (^ to ^ 106557.doc -10- 1312682 alkyl, which is selected from a group consisting of 〇R8, -NR8R8 and -SR8; wherein r8 is independently selected from the group consisting of hydrogen and (: 丨 to ^ alkyl; HET2 is a monocyclic or bicyclic heteroaryl group, wherein the monocyclic ring And the bicyclic heteroaryl group is optionally substituted by at least one R5, provided that HET2 is not tetrazole; R is selected from the group consisting of halogen, thiol, cyano, oxime to C8 alkyl, C2 to C8 alkenyl, C2 To Cs alkynyl, (^ to (:8 alkoxy, (:3 to (:8 cycloalkyl), C3 to cs cycloalkyl-(^ to 匚8 alkyl, CdC8 alkylthio, -NR7R7 and CdC8 a group consisting of a haloalkyl group;

B1 and B2 are atoms adjacent to Het1' which are respectively selected from the group consisting of carbon and nitrogen; j bond is a covalent bond between Z and B2; k bond is a covalent bond between B1 and B2 in Het1 And X and X1 are each selected from the group consisting of oxygen, sulfur, C(R 2 ) 2 and NR 2 , respectively, with the proviso that at least one X or χ is carbon;

Υ is a group selected from the group consisting of carbon and nitrogen; the limitation is that when γ is carbon, it is substituted by R6; wherein each R6 is selected from the group consisting of argon, halogen, hydroxyl, cyano, c丨 to C8 alkyl,. 2 to (:8 alkenyl, C2j_C8 alkynyl, CiJ_C8 alkoxy, to. Cycloalkyl, C3K8 ring alkyl, q to (tetra)thio, ^ to, -S(0)m_R7 and c(〇) _nr7r7, wherein the hetero atom is selected from nitrogen, oxygen and a sub-substituent substituted by a substituent, which is substituted by a c8 haloalkyl group, a -NR7R7, a _〇_cf3 hetero atom (^ to (8 alkyl, sulfur) a group consisting of and wherein the hetero atom is selected from the group consisting of hydrogen, (: silk C3K8 cycloalkyl, C2 to (10), CJC8, and (^ to (: 8 haloalkyl group; 106557.doc -11 - 1312682 wherein the parent R is independently selected from the group consisting of hydrogen and CrC8 alkyl; p is 1, 2 or 3; η is 0, 1 or 2; and m is 〇, 1 or 2. In another embodiment The invention provides a compound or a pharmaceutically acceptable salt thereof;

Where Z is 丫丨/YW1\XA^\"

II (R1)P

'Y^\Y,Y

Each of the R1 systems is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, ^ to alkyl, C2 to cs alkenyl, G to Cs alkynyl, fluorenyl to decyloxy, decyl, C3 to C8 Cycloalkyl, Q to Cs cycloalkyl-Ci to Q alkyl, 4 to 7 membered heterocycloalkyl, CdCW thio, _NR3R3, _〇_Cf3, C(0)-NR3R3 and substituted with a hetero atom a group consisting of alkyl groups, wherein the hetero atom is selected from the group consisting of t, oxygen, and sulfur, and wherein the hetero atom y is further substituted with a substituent selected from hydrogen. To 匕alkyl, ^ to C* alkyl,. to. Alkenyl,. 2 to. 8 alkynyl and c 丨 to. a group consisting of haloalkyl groups; 106557.doc • 12- 1312682 Each R3 is independently selected from the group consisting of hydrogen, hydrazine 1 to (8 alkyl, to alkenyl, to Cs alkynyl, to argon (: 8) a haloalkyl group, a to Cs cycloalkyl group; R2 is selected from the group consisting of hydrogen, (: 丨 to 匚8 alkyl, (: 3 to (: 8 cycloalkyl-(^ to. alkyl, C2 to a group consisting of a Cs alkenyl group, a Q to a alkynyl group (^ to an alkenyl group, a ^alkyl group, and a cycloalkyl group); the HET1 is selected from the group consisting of a monocyclic heteroaryl group and a bicyclic heteroaryl group. a group wherein the monocyclic and bicyclic heteroaryl groups may optionally be substituted by at least one R4; R is selected from the group consisting of Ci to C8 haloalkyl; HET is a monocyclic or bicyclic heteroaryl group, wherein The monocyclic and bicyclic heteroaryl groups may be substituted by at least one R5; R5 is independently selected from the group consisting of halogen, hydroxy, cyano, (^ to ^alkyl, ^ to. alkenyl, C2 to Cs alkynyl, (^ to a group consisting of (8 alkoxy, c3 to C8 cycloalkyl, C3 to C8 cycloalkyl-C^C:8 alkyl, CdC8 alkylthio, _NR7R7 and Ciic8_alkyl; B1 and B2 are with Het1 Adjacent atoms, each selected from the group consisting of carbon and nitrogen; j bond is a total between Z and B2 Key; k bond is a covalent bond between B1 and B2 in Het1; X and X are each selected from the group consisting of oxygen, sulfur, C(r_2)2 and nr2, respectively, with the restriction that at least one X or X1 is carbon; Y is a group selected from the group consisting of carbon and nitrogen, and is limited by the fact that when Y is carbon, it is substituted by R6; wherein each R6 is selected from the group consisting of hydrogen, halogen, thiol and cyano , c 1 to alkyl, C 2 to C 8 alkenyl, C 2 to Os alkynyl, (:! to (: 8 alkoxy, (^ to heart 106557. doc -13 - 1312682 cyclofilament, (tetra) _Cl to (10) a group, q to (10) thio group, ^ to c8 dentate group, NR ν·〇·π3, _S(〇)m_R> c(〇)_nr7r7, a hetero atom-substituted CJC8 alkyl group, wherein the hetero atom is selected from the group consisting of a group consisting of nitrogen, oxygen and sulfur, and wherein the hetero atom may be additionally substituted by a substituent selected from the group consisting of hydrogen, CJC8 炫 CjC8 cycloalkyl, CjC8 dilute, C2^ alkynyl and (: 丨 to a group consisting of 匸8 haloalkyl; each of which is selected from the group consisting of hydrogen and CA alkyl; 1) is Lu 1, 2 or 3; η is 0 ' 1 or 2 and m is 〇, U2. In the aspect of the invention, γ is a group selected from the group consisting of carbon and nitrogen, and the limitation thereof The condition is 'no more than one γ is nitrogen. In another aspect of the invention, X1 is carbon and hydrazine is oxygen. In another aspect of the invention, all γ is carbon (ie, the heteroaryl group is quinoline). Provided are a compound of formula I or a pharmaceutically acceptable salt thereof, wherein het1 is a 5-membered heteroaryl group. Preferably, HET1 is selected from the group consisting of beta quinone, isoindol, saliva, saliva, thiazole and imidazole. The group. φ The present invention also provides subgenera to provide a plurality of ring atoms which can be used in the formula I ΗΕΤ 2, wherein the HET 2 is selected from the group consisting of 4" thiol groups, heart sprays and azoles. More preferably , HET2 is 4-pyridyl. In a preferred embodiment, the invention refers to a compound of formula i(a)-i(k): l〇6557.do, •14· 1312682

And

HET2 A compound of formula I wherein j, k, Z HET2 and R4 are as defined above. More preferably, it has the following general structure: -15 - 106557.doc 1312682

Most preferably, the compound of formula i has the following general structure:

On the other hand, in order to obtain the compound of the above formula 1, HET1 is not tetradecene. The chemistry of Formula 1 may have an optical center and thus may occur in different pairs of palm isomers and non-image mirror isomeric configurations. The present invention includes all of the palmier isomers, diastereomers and other stereoisomers of the compounds of the formula, as well as other mixtures of racemic compounds and racemic mixtures and stereoisomers thereof. The pharmaceutically acceptable salts of the compounds of formula I include the acid addition salts and the addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Such examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, citrate , camphor sulfonate, citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronide, Hexafluorophosphate, hibenzate, Cong/salt hydrochloride, hydrobromide/bromide, hydroiodide/iodide, hexacylic acid _ 106557.doc • 16. 1312682 (isethionate), Iactate, malate, maleate, malonate, mandelates, mesylate, strontium sulfate, naphthylate, 2 -naphthalene sulfonate, nicotinic acid salt, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, Pyroglutamate, salicylate, saccharate, stearate, succinate, sulfonate, stannate, tartrate, p-toluenesulfonate, trifluoroacetic acid Salt and xinofoate. Suitable test addition salts are formed from bases which form non-toxic salts. Such examples include, but are not limited to, aluminum salts, arginine salts, benzathine salts, calcium salts, choline 'diethylamine, glycolamines, glycine, lysine, magnesium salts, Portuguese Meglumine, ethanolamine, potassium salt, sodium salt, tromethamine and salt. It is also possible to form half salts of acids and bases, for example, hemisulfate salts and hemi-calcium salts. For review of the applicable salts, see the Handbook of Pharmaceutical Salts by Stahl and Wermuth. Sex, Negative, Choice and Use (Handb〇〇k of Pharmaceutical)

Salts : Properties, Selection, and Use) (Wiley-VCH, 2002). The pharmaceutically acceptable salts of the compounds of formula I can be prepared by one or more of the following three methods: (I) by reacting a compound of formula I with a desired acid or base; (II) removing the applicable formula using the desired acid or base An acid or base labile protecting group in the precursor of the compound I, or a ring of a suitable ring precursor, such as an internal or internal amine; or 106557.doc -17-1312682 (iii) utilizing and applying an acid or A salt of a compound of formula I is converted to another salt by a base reaction or by a suitable ion exchange column. All two reactions typically occur in solution. The salts which are obtained can be precipitated and collected by filtration or can be obtained by evaporation of a solvent. The degree of ionization in the resulting salt can vary from complete ionization to almost no ionization. The compounds of the present invention can exist in a continuous solid state ranging from completely crystallization to complete crystallization. The term "no crystal" means that the material lacks long-range order in the molecular layer and may exhibit physical properties of solid or liquid depending on temperature. Typically, the material does not give a different χ-light diffraction pattern and is more formally described as a liquid while exhibiting solid properties. When heated, it changes from a solid property to a liquid property, which can be characterized by a change in state, typically a secondary ("glass conversion"). The term "crystalline" means that the material has a solid phase with a regularly ordered internal structure in the molecular layer and gives a different X-ray diffraction pattern with defined peaks. When heated enough, the material will also exhibit liquid properties, but the change from solid to liquid can be characterized by phase change, typically one stage ("melting point"). The compounds of the invention may also be present in undissolved or dissolved form. The term "lysate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is used when the solvent is water. There is currently a classification system accepted for use in organic hydrates as a combination of hydrates defining channels, channels or metal ions - see KR Moms' medicinal solid pleomorphism (p〇lym〇rphism in ph playing maceutical 106557. Doc -18- 1312682

Solids) (Ed. Η. • G. Brittain, Marcel Dekker, 1995). Isolation site. Isolation site

Water molecules and metal ions are bonded.

Depending on the degree and drying conditions. In these cases, the water/solvent content will be non-stoichiometric and will be the standard. The compounds of the invention may also exist in a mesomorphic state (intermediate phase or liquid crystal), where appropriate. The mesomorphic state is an intermediate between the true crystalline state and the true liquid state (melting or solution). Mesomorphism occurs because of the temperature change, so it can be described as "therm" (therm〇tr〇pic) and it is caused by the addition of the first component such as water, or the addition of another solvent. , called "lyotropic". Compounds with the potential to form lyotropic mesogens are called "amphiphilic" and are characterized by ionicity (eg -COCTNa+, -COCTK+ or S03_Na+) or nonionic (eg _N-N+(CH3)3) The molecular composition of the polar end group. For more information, see Ν. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope, 4th Edition (Edward Arnold, 1970). All compounds of formula I mentioned below. Including its salts, solvates, multi-component complexes and liquid crystals, and its salts, multi-component composites 106557.doc • 19-1312682 and liquid crystal. The compounds of the invention include formula! a compound, as hereinbefore defined, includes all polymorphs and their crystalline habits, precursor drugs and their isomers (including optical isomers, geometric isomers and tautomers), as defined below, And isotopically labeled compounds of formula I. As indicated, the "precursor" of the compound of formula I is also encompassed within the scope of the present invention. So some may have little or no medical activity! The compound derivative, when administered to the body or on the skin, can become a compound of formula I having the desired activity, for example, by hydrolytic cleavage. This derivative is referred to as a "precursor drug." Additional information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in

Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche,

American Pharmaceutical Association) The prodrugs according to the present invention may, for example, utilize certain groups known to those skilled in the art, referred to as "precursor groups", in place of the appropriate g groups in the compounds of formula It was manufactured by H. Bundgaard's pre-drug drug (Elsevier, 1985). Some examples of prodrugs according to the invention include, but are not limited to: (1) in the compound of formula I containing a carboxylic acid functional group (_c〇〇H), the ester of which is a carboxylic acid functional group in the compound of formula I a compound in which the hydrogen may be substituted by a (Ci_c8)alkyl group; (Π) in the compound of formula I containing an alcohol functional group (-〇H), an ether thereof, for example, a hydrogen of a carboxylic acid functional group in the compound of the formula I may be Ci_C6) alkanoyloxy 106557.doc • 20- 1312682 methyl-substituted compound; and (iii) a compound of formula I containing a primary or secondary amino functional group: or -NHR, where R is) , its amines, for example, the style! A compound in which one hydrogen or two hydrogens of an amine functional group in the compound may be substituted by a (Cl_Ci())alkylhydrazine group. Examples of other examples of substituent groups and other precursor drug types according to the foregoing examples can be found in the aforementioned references. Furthermore, certain specific compounds of formula I may themselves be used as precursor drugs for other chemical compounds. Also, metabolites of the compounds of formula I are also included within the scope of the invention, i.e., compounds which are formed by administering the drug in vivo. Examples of some metabolites according to the invention include, but are not limited to: (1) a hydroxymethyl derivative (-CH3->-CH2OH) in the compound of formula I containing a methyl group; (ii) The compound of I contains a monoalkoxy group, a hydroxy derivative thereof (-0R->-0H); (iii) a secondary amino group derivative of the compound of formula I containing a tertiary amino group ( -NWrIs-NHR1 or -NHR2); (lv) a primary derivative of the compound of formula I containing a secondary amine group (-NHR1 ->-NH2); (v) a compound of formula I containing benzene a phenolic derivative (_Ph->-PhOH); and (vi) a compound of formula I containing a guanamine group, a carboxylic acid derivative (-CONH2->COOH); 106557. Doc-21 · 1312682 Fatty amine functional (Vii) in the compound containing an aromatic argon atom bite a base, its N-oxide derivative. In the tertiary amine functional group, a gas is substituted by oxygen (ie, N·oxide); the compound of formula 1 may further contain one or more asymmetric carbon atoms, and the compound of formula I may be two bites and two solids. Isomers are present. Where the compound of formula 1 contains an alkenyl group or a dilute group, it is possible to produce a geometric cis/trans (or Z/E) isomer. : When the low-energy barrier is mutually convertible, the object >2~j can undergo a mutual transformation ("tautomerism"). This may be in a compound containing, for example, a structure such as an oxime group, a sulfhydryl group or a aryl group containing a aryl group. Next, the co-construction of a single enthalpy can be expressed in more than one isothermal furnace: the stereoisomers, geometric isomers, and tautomeric constitutive forms of the compound are included in the present invention. The formula ", the compound of the structure" and its or its species, is also included, "the dual ion is a salt or a salt of a 1-alternate or a racemic acid," , d-lactate. , for example, d1·tartrate or dl-sperm/trans isomer can be obtained by using 孰..., example*, chromatography = well-known conventional techniques for crystallisation) 〇 'separation crystallization method (fractional for preparation / separation) The use of optically pure precursors for individual palms is a customary technique that involves the use of palatable or utilized, for example, palmar high pressure fluid 106557.doc -22· 1312682

2 Analytical method (HPLC) allows the racemate (or racemate or derivative racemate) to be isolated. J. Alternatively, the racemate (or racemic precursor) may be reacted with a suitable material such as 'alcohol' or in this case, a compound of formula z; an acidic or a test group Groups, -acids or assays, such as !-phenylethylamine oxime- & non-imagewise isomeric mixtures can be separated by chromatography and separation crystallization, and are well known to those skilled in the art. The way it is to convert a non-image isomer or both into a corresponding pure palmomer. The acquisition of the palm compound of the present invention (and its anterior reclining body) can be performed by chromatography in the palm/structured form, typically as a book [匸, in an asymmetric tree with a moving phase曰上' is composed of a hydrocarbon group, typically money or calcined, which contains isopropanol from hydrazine (10) by volume, typically from 1% to 20%, and from hydrazine to 5% by volume of amine amide. Typically, it is (M% diethylamine. The concentrate of the solution provides a reinforced mixture. When any racemate is crystallized, two different crystals may be obtained. The first one is the above mentioned a compound (true racemate) in which a homogeneous form of crystals is produced, which is a two-pair palm isomer of the same molar number. The first species is a racemic mixture or agglomerate, which can be produced. Two kinds of 弋, σ, which have a molar number and each contain a single pair of palm isomers. When the two crystalline forms of the racemic mixture have different physical mussels, we can have Compared with the real racemate, the physical properties of the shell-free compound can be utilized. Isolation is familiar with the familiar techniques familiar to those skilled in the art. See, for example, 'E, L Eiie%s_ Η··, 106557.doc -23- 1312682 (Stereochemistry of 〇rganic c〇mp〇unds) (Wiley, 1994) ° The present invention encompasses all pharmaceutically acceptable isotopically labeled formulas [wherein- or more than one atom may be replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number which is naturally dominant. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2H and 3H, carbon isotopes such as uc, nc and "C' gas isotopes, such as 36 (: 1, gas Isotopes such as strontium, iron isotopes such as % and (1) D nitrogen isotopes such as % and %, oxygen isotopes such as %, % and 丨8〇, phosphorus isotopes such as 32p and sulfur isotopes, for example 35s. Special isotope; ^ 5 formula; compounds, for example, combined - radioactive with ', 〇 specialized 13 substances, can be used in drug and / or substrate distribution research. Radioisotope gas, that is, 3H, Carbon·14, ie, "C, is specifically used for the purpose of such easy combination and convenient detection. Utilizing the isotope of slave weight such as hydrazine, that is, the substitution of 2H, some can be stabilized by large metabolism. The therapeutic benefits of sex, for example, increase in vivo half-life / or reduce dose requirements, and therefore are a better choice in some cases. Use positron emission isotope, such as "c, 1汴, 丨5〇 and Substituting, P〇sitron Emission Topography (PET) study to examine the receptor occupancy rate. Isotopic labeling formula compounds can usually be prepared by the skilled artisan, or utilized These methods are prepared analogously to the methods described in the Examples and Preparations 106557.doc -24 - 1312682 using a label-free reagent suitable for use. The 4-primed labeling reagent replaces the previously pharmaceutically acceptable solvate according to the present invention: it can be substituted by an isotope, for example. ~Acetone Specific specific examples of the invention include and the pharmaceutically acceptable salts, the compounds exemplified in the formula: =:

Isomers, metabolites, precursor drugs and other derivatives::. Polymorphism, Lijing II: crack treatment f mental illness and conditions, such as consideration, such as panic abnormalities and coercion:,,, 荜 group of people scooped into (four) dance - m di_ medical beam group 0, Contains a valid I ^ 匕 σ to effectively inhibit PD £ 1 〇. In another embodiment, the invention relates to the treatment of a psychiatric disorder or

These include ligands in which crystallization is dissolved, d6-DMSO, such as schizophrenia, delusional disease, and drug 2 psychosis; anxiety abnormalities such as panic abnormalities and obsessive-compulsive disorder; and abnormal activity disorders, including Parkinson's disease And Huntington's disease contains a potent compound of formula I to effectively treat the disease or condition. Examples of psychiatric disorders that can be treated in accordance with the present invention include, but are not limited to, schizophrenia such as delusional, disorganized, stiff, mixed or latent schizophrenia; schizophrenia; schizoaffective disorder Such as illusory or melancholic schizoaffective disorder; paranoia; substance-induced psychosis; such as alcohol, amphetamines, amphetamines, marijuana, coca, hallucinogens, inhalants, opium or stupid cyclists (ie angel powder) The mental illness caused; 妄106557.doc -25- 1312682 t-type personality is abnormal, and the split personality is abnormal. Examples of activity-unique diseases that can be treated in accordance with the present invention include, but are not limited to, those selected from Huntington's disease and dyskinesia associated with dopamine agonist treatment, Parkinson's disease, lower limb restlessness 35 syndrome, and idiopathic Zhenyan. Other diseases that can be treated in accordance with the present invention are obsessive-compulsive disorder, Tourette's syndrome, and other tic disorder. In another embodiment, the invention is directed to a method of treating anxiety in a mammal: an anxiety condition comprising administering to the mammal an effective amount of a compound of formula I effective to inhibit PDE 1 〇. The invention also provides a method of treating a mammal also providing a treatment for anxiety or anxiety, the method comprising administering to the mammal an effective amount of a "complex to effectively treat the disease or condition. It can be treated in accordance with the present invention. Examples of anxiety abnormalities include, but are not limited to, panic disorder 'square phobia; specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder: acute stress disorder; and generalized anxiety disorder. Including a method for the canceration of a human drug, such as alcohol, amphetamine, coca test, or a tablet addiction, the method comprises administering to the mammal an effective amount of sputum. The present invention is effective in treating the drug into pain. Providing treatments for mammals, including humans, addiction; ί, such as alcohol, amphetamine, coca test <- slice addiction, the method comprises a technique for giving the mammal an effective amount. Effectively suppressing drug addiction" as used herein, thinking about the abnormal thirst of drugs. 106557.doc -26- 1312682 Hope and its special desire is usually motivation Tone, such as forced medication and a strong desire to take music was the desire to attack. The present invention further provides a method for treating a mammal, including a human, a disease, a disease characterized by a subjective thinking and/or cognitive deficiency, the method comprising administering to the mammal an effective amount of a compound of the formula to be effective Treat the disease. The invention further provides a method of treating a mammal, including a human, a disease or condition, comprising a disease characterized by & mentor and/or cognitive deficit, the method comprising administering to the mammal an effective amount z compounds to effectively inhibit PDE10. The invention also provides a method of treating a mammal, including a human, a disease or condition, comprising a condition characterized by attention and/or cognitive deficit, the method comprising administering to the lactophile an effective amount of a compound Effective treatment of the disease or condition. The term “attention and/or lack of cognition” as used in this article “includes a disease characterized by attention and/or lack of awareness” means that a particular individual has more than one or more cognitive aspects than other individuals of the same age group. For example, memory, intelligence or learning and logic capabilities, below normal function. "Attention and/or lack of recognition" also refers to a reduction in the performance of one or more of the cognitive aspects of any particular individual, such as a decline in cognitive ability that occurs in age. An example of a disease comprising symptoms of attention and/or lack of cognition and which can be treated according to the invention is dementia, such as Alzheimer's disease (Aizhei, Sa Se), dementia, vascular dementia (vascular dementia) Alcohol dementia or other drug-related dementia, related to cancer or brain creation. 106557.doc -27- 1312682 Dementia, cancer of Huntington's disease or Parkinson's disease, Or AIDS-related dementia; sputum; memory loss disorder; post-traumatic stress disorder; mental retardation; learning disabilities such as dyslexia, mathematics or writing disability, U-minority/hyperactivity disorder; and age-related cognitive abilities reduce. The invention also provides a method of treating a mood disorder or mood in a mammal, including a human, comprising administering to the mammal an effective amount of a compound to effectively treat the disease or episode. The invention also provides a method of treating a mood disorder or mood in a mammal, including a human, comprising administering to the mammal an effective amount of a compound to effectively inhibit PDE10. Examples of mood disorders and mood episodes that can be treated in accordance with the present invention include (but are not limited to) mild, moderate, or severe forms of severe stagnation, arrogance or mixed episodes, mild arrogance episodes Adolescent episodes with atypical characteristics; melancholic episodes with depression; frustration with a stiff trait, episodes of postpartum episodes; post-stroke depression; severe depression, low-altitude emotions; Depression; premenstrual anxiety; mental score: post-depressive disorder; severe depression plus psychosis, such as paranoia or mental knife disease, prostatitis, such as type 1 bipolar disorder, type II bipolar disorder and circulatory mood disease. Further, the present invention provides for the treatment of a mammal, including a human neurodegenerative disease, or a method comprising administering to the mammal an effective amount of a compound of the formula to effectively treat the condition or condition. Further provided is a method of treating a mammal, including a human neurodegenerative disease or condition 106557.doc! 312682, an effective amount of a compound of formula I, comprising administering to the mammal effective inhibition of PDE10. As used herein, and 昤#陈非 otherwise stated, otherwise "neurodegenerative disease or condition" refers to a disease caused by neuronal dysfunction and/or death in the middle of the nervous system a, evaluation, or Happening. The treatment of such diseases and conditions can be promoted by the administration of a pharmaceutical agent, and in the prevention of dysfunction of dangerous neurons in such diseases or conditions, the death of the disease and/or the use of compensable instruments Dangerous

The dysfunction of a dangerous neuron or the death of a 40% loss of function reduces the function of a tattoo or healthy neuron. A "neurotrophic agent" as used herein refers to a medicament having such properties. Examples of diseases and conditions in which some or all of the properties of the Temple & quality may be treated according to the present invention include (but are not limited to) Parkinson's disease • Henry n. Λ Dington's disease, dementia Symptoms, such as Alzheimer's disease, multiple stroke dementia dementia and predecessor obesity. Related Μ treatments, A ί DS - related] Alzheimer's nerves related to brain trauma

Related to the neurodegenerative diseases of stroke. Degenerative diseases, sputum exhibition, diseases related to cerebral embolism'·low blood (four) vaginal retreat, two devout, g children - Yang on the epileptic seizure, ... 匕 disease ; related to neurotoxin poisoning neurological and multi-system atrophy. Disease, in a specific example of the present invention, the mammal includes a neurodegenerative disease in which the disease or condition comprises a neurodegenerative heart of the striate sinusoidal neuron f. The present invention is another specific financial, neurodegenerative disease chorea. The present invention also provides for the treatment of mental illness 106557.doc -29· 1312682 triggering psychosis; anxiety, abnormal disease, obesity and (4) ^ (4) different i nerve r 』 ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 A method of treating a disease, the method comprising administering a compound of formula I in an effective form to treat the disease. The present invention «treatment _ from the next _ Li Shuqun method Haimo's disease, multiple stroke dementia (blood pure dementia), alcoholic dementia or other 筚勒 ^ Μ #related cancer, related to Gu Internal tumor or brain injury, dementia, related to Hending @ Irrespective of Dyton's snoring or Parkinson's disease, dementia s • related dementia; sputum; memory loss disorder; post-traumatic stress disorder, intelligent retardation; Learning disabilities, such as dyslexia or writing disability; attention deficit/hyperactivity disorder; age-related cognitive decline, mild, moderate or severe type of severe stagnation; manic or mixed mood episodes; mild arrogance Seizure period; worries with atypical characteristics# seizure period with depression characteristics; depression with special symptoms of w; t; episodes of postpartum depression; depression after stroke; severe disease;

If sense 'mild depression, premenstrual anxiety; post-schizophrenia depression; severe depression plus psychosis, including paranoia or schizophrenia; dysentery includes type I bipolar disorder, type II bipolar disorder, Circulatory mood, Parkinson's disease; Dyton's chorea; dementia, Alzheimer's multiple stroke dementia (vascular dementia), AIDS-related dementia, anterior dementia; Neurodegenerative diseases of brain trauma; neurodegenerative diseases associated with stroke; phase 106557.doc •30· 1312682 Neurodegenerative diseases of cerebral embolism, hypoglycemic pathogenesis, neurodegeneration associated with epileptic seizures Neurodegenerative diseases of venom poisoning, and more, related to neurotoxins 'Ning, 'death sputum / s disease, tolerance, stiff, mixed type or latent punishment 1 female heart type, disordered type, flying kidney I'm schizophrenia; Fantasy or melancholy splitting emotions, Luna is a split; Disease; Alcohol, Amphetamine, Dawei, Quality-induced spirit L Coco test, Fantasy, Fensheng, Inhaler, Opium ! A compound of formula I, which is formulated with a compound of formula I, is effective in the treatment of such diseases. Effectively, the present invention also provides a treatment for mental illnesses. 隹 杳 ^ ^ ^ 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 〖 In one method, the method comprises administering a compound of formula 1 to f to inhibit PDE10. The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbyl groups having straight or branched chain groups. Examples of alkyl oxime include, but are not limited to, methyl, ethyl, propyl, isopropyl, and tert-butyl. The term "alkenyl" as used herein, unless otherwise indicated, includes An alkyl group having at least one carbon-carbon double bond, wherein the alkyl group is as defined above. Examples of dilute groups include, but are not limited to, vinyl and propenyl. The term "alkynyl" as used herein, unless otherwise indicated, includes an alkyl group having at least one carbon-carbon triple bond wherein the alkyl group is as defined above. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl. The term "alkoxy" as used herein, unless otherwise indicated, is used alone or as part of another group, as used herein, or an alkyl group to which an oxygen atom is bonded. The term "hospital sulfur" as used herein, unless otherwise indicated, as used herein alone or as part of another group, includes any alkyl group attached via a sulfur atom. The term "halogen" or "i group" as used alone or as part of another group refers to gas, bromine, fluorine and iodine. The term "haloalkyl" as used herein, unless otherwise indicated, refers to at least one link. The base of an alkyl group. Examples of dentate groups include, but are not limited to, trifluoromethyl, trifluoroethyl, difluoromethyl, and fluoromethyl groups. The term "cycloalkyl", as used herein, unless otherwise indicated, includes a non-aromatic saturated cycloalkyl group, the t alkyl group of which is as defined above. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane 2, and cycloheptyl. < Α The term "aryl" as used herein, unless otherwise indicated, includes an organic group derived from an aromatic hydrocarbon group by removal of a hydrogen such as phenyl, naphthyl, benzyl and sulfenyl. . "Aryl" encompasses a fused ring group wherein at least one of the rings is aromatic. The term "heterocyclyl", "heterocycloalkyl" and like terms, as used herein, refers to a non-aryl ring group containing one or more heteroatoms, preferably from one to four heteroatoms. Preferably, each atomic system is selected from the group consisting of oxygen, sulfur and nitrogen. The heterocyclic group of this month may also include a ring system substituted with one or more oxygen groups. Examples of non-aromatic heterocyclic groups are anthracene propane group, nitrogen group, pyrrolidine 106557.doc -32. 1312682 _ acridinyl, azirretyl, piperylene, 12,3,6-tetrahydropyridyl , Ethylene oxide, oxetan, tetrahydrofuranyl, tetrahydroindolyl, tetrahydropyrene, thiopyran, morpholine, thiophene, thiourea Mercapto (叮1) ° specific porphyrin group, porphyrin group, 2H-pyranyl group, 4H-pyranyl group, dioxanthene group, i,3-dioxolanyl group, fluorene group, two Hydroquinone, dihydrothienyl, dihydrofuranyl, pyrazolyl, imidazolinyl, imidazolidinyl, 3-nitrodicyclo, 3-azabicyclo[4·1·〇] Base, 噎琳耕基, pyridine group, Μ_二吟螺和[4·5] 癸 base, U-二崎螺 and [4.4] 壬, 1,4-二呤螺[4.3] octyl And 丨, 4_二噚螺和[42] heptyl. The term "heteroaryl", as used herein, refers to an aromatic group (preferably oxygen, sulfur and nitrogen) containing one or more heteroatoms, preferably from one to four heteroatoms. A polycyclic group containing one or more heteroatoms wherein at least one of the rings is aromatic' which is a "heteroaryl" group. The heteroaryl groups of the present invention may also include ring systems substituted with - or more oxygen groups. A heteroaryl group containing a third order nitrogen may also be additionally substituted by oxygen (i.e., ruthenium oxide). Examples of heteroaryl groups are pyridyl, hydrazine, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyridinyl, quinolinyl, isoquinolinyl, tetrazolyl, furyl, thiophene Base, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, fluorenyl, fluorenyl, benzimidazolyl, benzofuranyl, porphyrinyl, oxazolyl, indolizinyl , morphine.三耕基,异吲#基基基基基基基基' π 咱 咱, benzoheptinyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quin Oxazolinyl, quinoxalinyl, acridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, furoacridine 106557. Doc -33· 1312682 (furopyridinyl), pyrrolopyrimidinyl and aziridine. For the sake of clarity, the term heteroaryl includes the heteroaryl structure of substituent 2 in formula I (i.e., the heteroaryl structure containing Y). Unless otherwise stated, the term "one or more" substituents, or "at least one" substituent, as used herein, refers to a substituent from one to the largest possible number based on the available binding sites. Unless otherwise stated, all of the foregoing groups derived from a hydrocarbyl group may contain up to about 1 to about 20 carbon atoms (eg, Cl_C2G alkyl, C2_C2G alkenyl, alkyl, 3_2 anthracene heterocycloalkyl; aryl, 5_2〇) a heteroaryl group, etc.) or from 1 to about 15 carbon atoms (eg, Ci-Ci5 alkyl, c2-C15 alkenyl, (: 3-(:15 cycloalkyl, 3-15 membered heterocycloalkyl, C6_Ci5 aryl, 5_15 member heteroaryl, etc.) 'or 1 to about 12 carbon atoms, or i to about 8 carbon atoms, or i to about 6 carbon atoms. "Neurotoxin poisoning" refers to poisoning caused by neurotoxins. Toxins are any compound or substance that can cause nerve death and thus cause nerve damage. An example of a neurotoxin is alcohol, and alcoholism in pregnant women can cause alcoholism and nerve damage in newborns, the so-called fetal alcohol syndrome. Examples of neurotoxins Including, but not limited to, kainie acid, d〇moic acid, and acomoic acid (ac_eiic heart); specific insecticides such as DDT · 'specific insecticides, such as organic phosphoric acid Esters; volatile organic solvents 'examples* six (eg toluene); heavy metals (eg, ship, mercury, shishen and scales); specific chemical substances used as weapons, such as agents (agent 〇range) and neurotoxic agents (Nem; sputum and neurotoxic anti-cancer 106557.doc -34· 1312682 As used herein, the term "selective PDE10 inhibitor" refers to a substance, such as an organic molecule, which is effective in inhibiting enzymes from the PDE 10 family to from the PDE 1-9 family. A larger amount of enzyme than the PDE 11 family. In one embodiment, the selective PDE10 inhibitor is a substance which is, for example, an organic molecule having a Ki value that inhibits PDE10, that is, less than or about 1/10 Ki. To make the substance useful for inhibiting any other PDE enzyme. In other words, the substance inhibits PDE10 activity to the same extent as the concentration required for any other PDE enzyme is about 1/10 or less. A Ki value of less than or about 10 μΜ, preferably less than or about 0.1 μΜ, may be considered to be effective in inhibiting PDE10 activity. A "selective PDE 10 inhibitor" may be identified, for example, a substance may be inhibited. PDE10 The ability of sex is compared to its ability to inhibit PDE enzymes from other PDE families. For example, the ability of a substance to inhibit PDE 10 activity can be analyzed, as well as inhibition of PDE1A, PDE1B, PDE1C, PDE2, PDE3A, PDE3B, PDE4A, PDE4B, The ability of PDE4C, PDE4D, PDE5, PDE6, PDE7, PDE8, PDE9 and PDE11 to be active. The term "treatment", as used in "methods for treating a disease", refers to the elimination, alleviation or inhibition of the progression of such diseases, which is the disease to which the term is applied, or one or more symptoms of the disease. As used herein, the term also encompasses the prevention of the disease or any symptoms associated therewith, as well as alleviating the severity of the disease or any symptoms prior to onset, depending on the patient's condition. "Treatment" as used herein means preventing the recurrence of a disease. For example, "treatment of schizophrenia, or schizophrenia or schizophrenic disease", as used herein, also covers treatment of one or more of the diseases 106557.doc -35 - 1312682 (positive symptoms, negative Sexual symptoms or other related features, such as treatment and & delusions and / hallucinations. Other examples of symptoms of schizophrenia and schizophrenia and schizophrenic disorders include disorganized speech, affective flattening, poor language (heart), lack of sexual pleasure (an11), inappropriate emotions, unpleasantness Emotions (dysPh〇ric mood) (such as 'emotions of depression, anxiety or anger form), and some symptoms of cognitive dysfunction. The term "mammal", as used herein, is the term "a mammal" Members of the class 'including, but are not limited to, humans, dogs, and tracings. The compounds of the present invention can be administered in a single dose, alone or in combination with a pharmaceutically acceptable carrier. Le General's pharmaceutical uploading agents include inert solid diluents or fillers, ginseng p.·, 囷水〉谷液 and various organic solvents. Therefore, the formed pharmaceutical composition is followed by P paper, and A can be administered in various dosage forms. For example, a syrup formulation, a liquid preparation, a syrup, an injectable solution, and a pot analog. These pharmaceutical compositions may optionally contain other additional ingredients, such as Flavoring agents, binding agents, 觥d excipients and the like. Thus, the compounds of the invention may be formulated; ^ σ HE Λ ^ in oral, buccal, intranasal, injection (eg intravenous, intramuscular or Subcutaneous injection), skin (eg patch) or rectal administration, or formulated for inhalation or injectable administration.

U and medicine 'the medicine' composition can be used in the form of 17 or 1 capsule, which can be prepared by using the conventional method, the soil method A and the pharmaceutically acceptable excipient.

For example, a binding agent (such as cat M " corn starch, polyvinylpyrrolidone or hydroxypropyl methyl fiber), a filler (such as lactose, microcrystalline cellulose or calcium phosphate); a lubricant (such as hard fat month) Knocking magnesium, talc or silicone); disintegrating agents (eg 106557.doc -36· 1312682 potato starch or sodium starch glycolate); or moisturizing agents (eg twelfth sodium sulphate). Such lozenges can be added to the syrup according to methods well known to those skilled in the art. Liquid preparations for oral administration can be used, for example, in the form of solutions, sugar concentrates or suspensions, or can be formulated as a dry product for use in combination with water or other suitable vehicle before use. The liquid preparation may utilize conventional methods and pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible oil); emulsifiers (e.g., lecithin or arabin

Tree), a non-aqueous vehicle (for example, almond oil, oily ester or ethanol); and a preservative (for example methyl or propyl p-hydroxybenzoate or propyl or hexadienoic acid). For buccal administration, the composition may be in the form of a lozenge or buccal tablet and formulated in a conventional manner. The compounds of the invention may be formulated for parenteral administration by injection, including the use of s: catheter technique or irrigation "master, method." Formulations for injection may be presented in unit dosage form, such as ampoules or multi-dose containers' and contain added preservatives. The y is in the form of & suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be reconstituted in powder form prior to use and in a suitable vehicle such as sterile non-pyrogenic water. When a product solution is desired, the isolated inclusion complex can be dissolved in water (or other aqueous medium) in a solution sufficient to be used for oral or injectable administration to a patient. The compound can be formulated for use in a fast dispersing agent ((10))' which is designed to release the active ingredient in the oral cavity. The material is often formulated using a fast dissolving gelatin matrix. These dosage forms have been known to us as 106557.doc -37-!312682 and can be used to transfer a wide range of agents. The fastest dispersing dosage form is the use of gelatin as a carrier or structural forming agent. Typically, gelatin can be used to administer the dosage form with sufficient strength to prevent breakage upon removal of the outer package, which can be dissolved immediately upon release of the gelatin. In addition, a variety of starches can be used to achieve the same effect. The compounds of the present invention may also be formulated to be straightforward, straightforward, and 5, such as suppositories or retention enemas, for example, containing conventional suppositories 曰π μ enamel, such as cocoa milk or other

Glycerin vinegar. For intranasal administration or inhalation administration, the compound of the present invention can be conveniently delivered in the form of a solution or suspension from a pressurized nasal spray, that is, by extrusion or pressurization by a patient, or by an aerosol by a grinder or spray. Spray in the mister' and use suitable propellants such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethylene, carbon dioxide or other suitable gases. In the case of an aerosol, the dosage unit can be determined by providing a value that can be used to dispense a metered dose. The pressurizer or nebulizer may contain a solution or suspension of the active compound. Capsules and g for inhalation or insufflation (e.g., made of gelatin) can be formulated as a powder of the compound of the invention and a suitable powder base such as lactose or starch. Spray formulations for treating such conditions (e.g., migraine) that occur in a typical adult are preferably arranged such that each metered dose or "spray" spray contains from about 20 mg to about 1 mg. A compound of the invention. The overall spray dose per ounce should range from about 100 mg to about 1 mg. The drug can be administered several times a day, for example 2, 3, 4 or 8 times, for example, 1, 2 or 3 doses each time. For oral, injection, rectal or buccal administration in the general adult to treat 106557.doc -38 - 1312682 the daily predetermined dose of the compound of the present invention, each unit of d can be administered from about 0. 01 From about 0.1 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I, for example, '1 to 4 times per day. Some assays are currently available for screening for substances that can be used to inhibit the hydrolysis of cyclic nucleotides, using PDE 10 and pDE from other gene families. The cyclic nucleotide used in this assay was subjected to a concentration of Km of 3 to compare its ι〇5〇 value between different enzymes. The pde activity can be measured by the method of Scmtillation Proximhy Assay (Fawcett et al., 2). The effect of the pDE inhibitor can be determined by detecting a fixed amount of the enzyme (PDEs 1-11). The concentration of various substances and the presence of low acceptor are determined, so that the IC5〇 is close to Ki (eGMP or cAMP is labeled to the [3h]_label at a concentration of 1/3 Km in a ratio of 3:1) (> The assay volume was adjusted to 100 μιη using assay buffer [50 mM buffer buffer - HC1 pH 7.5, 8.3 mM MgCl2, 1 mg/ml bovine serum albumin]. The enzyme can be used to initiate the reaction, which is incubated at 30 ° C 30- The reaction was terminated by 60 minutes to obtain < 30% substrate turnover utilization and using 50 μ of gelatin SPA beads (Amersham) containing 3 m Μ unlabeled cyclic nucleotides for PDE 9 and 11, respectively. The plate was resealed and shaken for 20 minutes, after which the beads were placed in the dark for 3 minutes,

TopCount microplate counter count (Packard, Meriden, CT). The active unit can be converted into a percentage activity without inhibition control (1 〇〇%), and the concentration of the inhibitor can be determined, and the IC5 value of the inhibitor can be used to "fit curve" Microsoft Excel (the "Fit Curve' , Microsoft Excel) extended. Using this assay, the compounds of the invention can be determined to have - ICso can be used to inhibit PDE10 activity of less than about 10 micromoles. 106557.doc -39- 1312682 The invention also relates to a compound of the formula I. The invention also provides methods for the synthesis of compounds of formula I. For example, the present invention provides a method for forming a compound of Formula 1, comprising the step of reacting a compound of the formula,

Containing monomethoxymethyl-dimethylamine and hydrazine or substituted hydrazine (e.g., R20-NHNH2' wherein r2 is an alkyl group). The invention also provides a process which can be used to form compound J of formula J, comprising the step of reacting a compound of formula III,

Contains oxalic acid oxalate; axis and formula HET-nhnh2. This month also provides a method of forming a compound of formula 1 comprising the step of reacting a compound of formula IV.

ET2 I06557.doc 1312682 contains dimethoxymethyl-dimethylamine and hydrazine or substituted hydrazine. The invention also provides a method of forming a compound of formula I, comprising a method of reacting a compound of formula v

Containing a compound of formula VI

Wherein Q is a hydroxyl group or a halide. [Embodiment] Scheme 1 describes the preparation of the compounds of the invention of pyrazoles. The densification of the substituted phenol and 2-methylchloridene provides the desired bond. The hydrolysis of the esters and treatment with sulfinium chloride provides the desired chloric acid. The addition reaction of hydrazine, hydrazine-dimethyl-methylamine hydrochloride can provide Weinreb decylamine for coupling (Weinreb et al, Tet Lett., 1981, 22 (39) 3815). The anion is produced by 4-picoline and LDA, followed by the addition of Weinreb decylamine to obtain a ketone, which can then be treated with dimethoxymethyl-dimethylamine at reflux to form an alkene. An aminone intermediate. The pyrazole analogs are then obtained by treatment with each of the genus 106557.doc -41 - 1312682, thus obtaining the two isomers in various ratios. The isomers can be separated by crystallization, Biotage MPLC, preparative TLC or preparative HPLC. This reaction scheme is typically used for a variety of initial reactions with substituted phenols, substituted quinolines, and substituted hydrazines. Flow chart 1

Another option is the alkylation of the NH pyrazole by the substitution of the compound.

Prepared. - In the case of a group, in a solvent such as dimethylformamide, bismuth citrate is used as an electrophile. Some reactions require heating. 106557.doc -42- 1312682 Flowchart 2

2 As described in Scheme 3, a variety of heterocyclic species can be prepared from the enaminone intermediate. Pyrimidines can be prepared by heating in the presence of ethanol and sodium ethoxide together with substituted meglumine. Isocarbazoles can be prepared by adding ethanol, acetic acid, acetic acid, and amide. Only one isomer is formed in the heterosexual case. The 6-5 bicyclic system can be formed by heating together with an aminoguanoline, an aminopyrazine or an amine triterpenoid. I06557.doc •43· 1312682 Flowchart 3

Rings such as 3 5 -methyl 3 can be prepared according to Scheme 4. Methyl heteropoly 4·pyridyl heterocycles, ... W Yinji... Deprotected with diisopropyl guanidine (mhiw diiS0pr0pyI amide) and added to Weinre_amine (Weinreb et al, Tet Lett) 1981, 22 ( 39) 3815) to provide the desired enthalpy. Post-treatment with dimethoxymethyl-dimethylamine and hydrazine to provide heterocyclic pyrazoles. Pyrimidines and isoxazoles may also be as in Scheme 3. Prepared as described. 106557.doc -44 - 1312682 Flowchart 4

OMe 1) , Nl〇Me reflux _I_ 2) NH2NHR

Ν-»Bipyridylpyrazole can be prepared according to Scheme 5. The starting ketones can be prepared by the desired alkylation as described in Scheme 1. The ketone is treated with dimethoxymethyl-monodecylamine followed by a 4-0 ratio of dimethyl guanidine (see j Med_Chem. 2002, 45 (24) 5397) to provide the desired compound. Other Heterocyclic substitutions for the 4-pyridyl group can be obtained by using the necessary hydrazine. Flow chart 5

As described in Scheme 6, 3 literature methods were prepared (see j-substituted-N-. than bite D is more specific than salivary Med. Chem. 2004, 47, 2180). The intermediate was treated with 106557.doc -45-1312682 acetophenone (prepared according to Scheme 1) using sodium methoxide and oxalic acid di-T S ’. 4-» 比唆基肼 (see j. Med 2002, 45 (24) 5397) was added to provide a pyrazole with an ester at the 3-position. The ester can be converted to a guanamine by a hydrolysis reaction and coupling with an amine. It can be converted to an ester by reduction to an alcohol and alkylation reaction. The formation of an amine can utilize the formation of guanamine' followed by a reduction reaction or conversion to an aldehyde followed by reductive amination. All such transformations can be achieved by methods known to those skilled in the art of organic chemistry. Flow chart 6

The benzyl intermediate can be prepared by the method shown in Scheme i. The benzyl bond can be removed via a ruthenium-covered catalyzed catalyst such as at the beginning of the carbon or at the beginning of the hydration in a variety of solvents. The phenol can then be alkylated by heating with potassium chloride in acetone and potassium carbonate. At the same time, the light can be extended # (Mitsunobu chemistry) (Hughes5 D.L., The Mitsunobu Reaction.

Organic Reactions. Vol. 42. 1992, New York. 335-656.) Applied to the coupling of various types and alcohols. 106557.doc -46 · 1312682 Flowchart 7

Or |\j Compound or alcohol Λ Λ 仓 贝 贝 贝 贝 贝 贝 贝 贝 贝 匁 匁 匁 匁 匁 匁 匁 匁 匁 匁It is known to those skilled in the art that the general method for the intermediates of the ethers and the acids to form aldehydes is to reduce the formation of alcohols. Preparation ^ For the gingival base, the sulphide is used for the rolling action, and the radix E is used to supply the aldehyde, that is, then the borohydride is used.

.m ^ ρ ... fly for reference < ',. Mercapto halides can be formed via halogenation reactions (see Syn. Com 1995, 25 (21) 3427-3434) β 106557.doc -47- 1312682 Flowchart 8

X=C or .N

1) Se02, 140 〇C two "

2) NaBH4, EtOH

X=C or N

X=C or N

Digas methane reflux

Triazole analogs can be prepared by a variety of methods using &#. There is a way to describe this in Flowchart 9. The 丨丨 丨丨 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Treatment, providing 1, 2, 4 king eagle (Mc. 〇rg. Lett, 2004, 6 (17), 2969-2971). The 异构 异构 异构 r r r r r r r 叹 叹 叹 叹 叹Flow chart 9

The other monoazole isomers can be prepared starting from guanamine according to Scheme 1 and treated with two 106557.doc -48· 1312682 methylmethionine diformaldehyde followed by addition of aryl hydrazine. The domain isomer triazoles can be prepared by the functionality of the hydrazine starting material. Flowchart 1 0

MeO R1

The converted ketone isomers can be prepared according to Scheme (4). JACS, 1988, 110, 4008.). Coupling the initial to the phosphonate to provide the decyl ketone 1 provides the desired hydrazone. The hydrazine can then be utilized according to Schemes 1, 2 and 3 to provide the desired compound.

Flow chart 11

The flow chart describes a method for synthesizing a 4,5. diaryl ten-seat. In the illustrative example, 4-foxy-benzoic acid and 4-methyl benzoic acid are combined with formamide to produce a substituted decylamine (as indicated above). This conversion is known from the reference 106557.doc -49-1312682 (L Med Chem., 2002, 45, 1697). The dehydration reaction of formamide in a reaction can be adjusted by POCI3 to give methyl p-toluenesulfonate. Such compounds can be treated with a base to produce a carbazole. In the illustrated case, methyl p-toluene isocyanate was treated with isonicotinic acid aldehyde and potassium carbonate. The product of this reaction is a carbazole having a 4-benzyloxyphenyl group at the 4-position of the indazole ring and a 4-pyridyl substituent at the 5-position. These substituents may be simply substituted with different aryl-aldehydes in the order of steps one and three via other aryl groups. Aryl. The cleavage of the benzyloxy group can be achieved by standard methods of catalytic hydrogenation, and the obtained phenol can be easily obtained by using an alkyl dentate such as 2-(chloromethyl)quinolin and a fluorination treatment in DMF. Calcination. The method is not limited to the case illustrated, since the relative positions of the phenyl and pyridyl rings are interchangeable, and the rings may contain a plurality of aryl groups which exhibit various substitution patterns. Flow chart 12

Scheme 13 depicts a method of preparing a 4,5' substituted oxime having an alkyl substitution at the ten full ring 2-position. In the illustrated case, the benzinyl-phenyl)-2-pyridin-4-yl-ethanone can be treated with a solution of bromine in acetic acid according to conventional methods and brominated by 106557.doc • 50-1312682. The product, bromoacetone, can then be treated with a solution of ammonium acetate and sodium acetate in acetic acid to produce a methyl-substituted ring, as disclosed in the patent document (d) 9513067). The methyl group can be substituted with other alkyl groups. For example, substitution of ammonium acetate, sodium acetate, and acetic acid will result in an ethyl group substitution. The cleavage of the benzyloxy group can be achieved by standard methods of catalytic hydrogenation, and the resulting phenol can be readily alkylated by treatment with an alkyl group, as described above. The method is not limited to the case for illustration, because phenyl and n are smaller than the base ring.

The relative positions are interchangeable, and the rings may contain a plurality of aryl groups which exhibit various substitution patterns. Flow chart 13

The step of Scheme 14 is the formation of an imine/heterocycle. Compound 2, wherein R1 is alkyl, benzyl or allyl' can be concentrated using a solution of 4-pyridine in a solvent such as toluene and heated to reflux, and equipped with a Dean_stark apparatus to remove moisture for about 40 hours. After removing the toluene, the crude imine and the methyl isocyanide tosylate are mixed with a base such as a potassium phthalate-dimethoxyethane and a decyl alcohol solvent mixture, and heated under reflux for about 3 hours. Get 3A. 106557.doc -51 - 1312682 Step 2 of Scheme 14 is the phenol demethylation. If R1 is a methyl group, demethylation can be carried out with boron tribromide (BBj*3) in a non-coordinating solvent such as methylene chloride at about 20-40 ° C for about 3-48 hours. Good for about 24 hours to get 4 A. For example, if R2 is a benzyl group, the deglazing action can be carried out with pure trifluoroacetic acid and anisole at a temperature of about 75 ° C for about 3 to 48 hours, preferably about 24 hours to give 4A. If R1 is an allyl group, dealkylation can be combined with a palladium catalyst such as palladium acetate dichloropalladium bis(triphenylphosphine), wherein dichloropalladium bis(triphenylphosphine) is preferred, and a reducing agent 'For example, n-butylammonium formate, in a solvent such as tetrahydrofuran, 1,2-dichloroethane, methylene chloride or monoalcohol, wherein hydrazine, 2-dioxaethane is preferred at a temperature The range is from 2 (rc to 7rc to give 4A. Step 3 of Scheme 14 is phenol alkylation. 4-8 uses a base such as potassium carbonate, sodium carbonate, carbonic acid planer, sodium hydride or potassium hydride, of which carbonic acid Preferably, the sodium or sodium hydride is used in a solvent such as tetrahydrofuran, hydrazine, 2-dimethoxyethane, N,N-dimethylformamide, dimethylacetamide, N-decylpyrrolidone or two. Methyl sulfoxide, wherein dimethyl sulfoxide or N, N dimethyl decylamine is preferred, is at a temperature of from about 20 Torr to 70. (;, wherein about 2 VC is preferred, and is treated for about 3 to 48 hours' Preferably, it is about 24 hours, and 1 a is obtained. Step 4 of Scheme 14 is deprotonation/electrophilic entrapment of imidazole. A base such as diisopropyl amide can be used. Or lithium 2,2,6,6-tetramethylpiperidine, wherein lithium diisopropylamide is preferably used in a solvent such as tetrahydrofuran at a temperature of from about -78 Torr to (TC, wherein about _ 2: (: Preferably, treatment 3A, about 5 minutes to 30 minutes, of which about 10 minutes is preferred, followed by the addition of the desired electrophile R3-I to give 3B. Step 5 of Scheme 14 is phenol dealkylation The effect and use of the same procedure as described above in the second step 106557.doc • 52· 1312682 produces 4B. Step 5 of Scheme 14 is phenol alkylation and produces 1B using the same method as step 3 above.

Step 1 of Scheme 15 is the guanidation of the amine to form the guanamine. Compound 2A, wherein R1 may be methyl, benzyl or allyl, may be acid chloride or carboxylic acid, in the presence of a coupling agent, such as tri-n-propylphosphonic anhydride or monocyclohexyl carbon The imine' is preferably a tri-n-propylphosphonic anhydride in the presence of a test such as sodium hydroxide, potassium carbonate or sodium carbonate, triethylamine or diisopropylethylamine, wherein diisopropyl Ethylamine is preferred in a solvent system such as water/methylene gas, water/ethyl acetate, ethyl acetate, tetrahydrofuran or methylene gas, with ethyl acetate being preferred at a temperature of about 〇. Preferably, it is about 50 ° C to 30 ° C, and is preferably treated to obtain 5 A. Step 2 comprises a chlorination reaction which forms a vaporized imine which is reacted with an amine to form a hydrazine which is then treated with an acid to form a hydrazine. Compound 5a can utilize a gasifying agent such as PCls/POCh at a temperature of about 120. (: Treatment for about 4 hours. The gasifying agent is removed in vacuo and an excess of 1,1 -diethoxy-2-ethylamine in a solvent such as isopropanol is added and the mixture is at about 23. 3 Stir for about 5-24 hours. 106557.doc • 53- 1312682 Remove the solvent in vacuo and add concentrated hydrochloric acid and isopropanol and heat the mixture to about 90 ° C for about 24 hours to produce 6A. 3 is a phenol dealkylation. If R1 is a methyl group, dealkylation can be carried out using a dibrominated side (ΒΒι*3) in a non-coordinating solvent, such as methylene chloride at about 20-40 C. -48 hours, wherein about 24 hours is preferred to obtain 7A. If R2 is a benzyl group, dealkylation can be carried out using pure trifluoroacetic acid plus anisole at a temperature of about 75 C for about 3 to 48 hours, wherein Preferably, 24 hours gives 7A. If R1 is an allyl group, dealkylation can be combined with a palladium catalyst such as palladium acetate di-palladium bis(triphenylphosphine), wherein di-palladium bis(triphenyl) Phosphine) is preferred, and a reducing agent such as ammonium n-butylcarboxylate in a solvent such as tetrahydrofuran, 1,2-dioxaethane, methylene chloride or monoalkanol Wherein 丨, ^ dioxane is preferred to act at a temperature ranging from 2 〇〇c to 75 〇c to give 7A. Step 4 of Scheme 15 is phenol alkylation. Potassium carbonate, sodium carbonate, cesium carbonate 'sodium hydride or potassium hydride, wherein the carbonic acid planer is preferred, in a solvent such as tetrahydrofuran, hydrazine, 2-dimethoxy ethane, dimethylformamide, dimercapto Acetamide, hydrazine-methyl mernoterone or dimethyl sulfoxide is preferred. The methyl hydrazine is preferably at a temperature of from about 20 Torr to 70 ° C, preferably about 23 ° C, and is treated. 3_48 hours, of which about 24 hours is better, and 1C is obtained. 106557.doc • 54 - 1312682 Flowchart 1 5

Quinolinyl benzaldehyde can be reacted with acetone in the presence of reflux piperidine to

Providing the desired olefin. NH-ton-U$ is obtained by treatment with hydrazine. This may additionally utilize sodium hydride and an electrophilic agent, such as iodophorone, such as, for example, to provide a substituted pyrazole. Flow chart 16

As described in Fig. 17, the fast-base and the broken compound are coupled by S〇nagashil for the combination of the three desertified boron in the gas solution (8) to be alkylated to give... (3) chloromethyl thiol azide In the seal / in the case of two mash 1 with trimethyl gangue gas - to provide the desired triazole. 19〇C^佳约l5〇C processing 24_72, j 106557.doc -55· 1312682 Flowchart 17

General Experiments If not otherwise listed, the organic solution was dried using magnesium sulfate or sodium sulfate. Room temperature can be abbreviated as RT. HPLC-MS System 1 contains Zorbax Bonus-RpTM 4·6χ 150 mm column at 1 · 0 mL per minute, solvent A = MeCN 'solvent b = 〇 · 1 〇 / 〇 aqueous formic acid, 1: 9 A : B to 95 : 5 A : The linear gradient of B lasts 1 , minutes, using a diode array

Hewlett-Packard 11 00 HPLC system with mass detector. HPLc System 2 uses a linear gradient of 3: 7 A: B to 95/5 A: B for 15 minutes. When purifying by RP-HPLC, the shimadzu preparative HPLC instrument unit has an X-TerraTM 50 x 50 mm column, solvent A = acetonitrile, solvent b = water, each containing 0·1 ° /. Trifluoroacetic acid (r-acidic condition) or 〇1% concentrated ammonium hydroxide ("alkaline case"), 25%-85% A: linear gradient of Β over 10 minutes. The following examples illustrate the invention. However, it is to be understood that the invention is not to be construed as limited by the description Experimental Procedure Preparation 1 106557.doc -56- 1312682 4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester in 2-chloromethylquinoline (2 g, 9.3 mmole) of acetone (47 ml , 0.2 M) solution was added methyl 4-hydroxybenzoate (1.42 g, 1.0 eq.) and potassium carbonate (3.86 g, 3 eq.). The reaction mixture was heated (1) EtOAc (EtOAc) (EtOAc) The phase separation was carried out and the organic layer was dried, filtered and concentrated with magnesium sulfate. Dissolution in a 40 Μ column using a 5-30% ethyl acetate / hexane gradient to afford white crystals (1.66 g, 61%). 4 NMR (400 MHz, CDC13) δ 8·18 (d, J = 8.7 Hz, 1 H), 8-07 (d, J = 8.3 Hz, 1 H), 7.95 (Μ, 2H), 7.82 (d, J=7.9 Hz, 1 H), 7.74 (dt, J = 7.1, 1.7 Hz, 1 H), 7.62 (d, J=8.3 Hz, 1 H), 7-55 (dt, J = 7.9, 1.2 Hz, 1 H), 7.03 (d, J = 9.1, 2 H), 5.41 (s, 2 H), 3.84 (s, 3 H); MS: (M+H m/z = 294.2). Preparation 2 4 ((Quinolin-2-ylmethoxy)-benzoic acid in 4-(quinoline-2-ylmethoxy)-benzoic acid oxime ester (500 mg, 1.7 mmole) in THF (8.5 ml And sterol (3 ml) was added with IN NaOH (3.4 ml, 2 eq.). The reaction mixture was allowed to fall for 16 hours at the nuclear temperature. The mixture was added to a mixture of EtOAc (m.). 4 NMR (400 MHz, DMSO) δ 8.39 (d, J = 8.3 Hz, 1 H), 7.99 (m, 2 H), 7.81 (Μ, 2H), 7.76 (dt, J=8.3, !·7 Hz, 1 H), 7.64 (d, J = 8.3 Hz, 1 H), 7_60 (dt, J = 7.9, 1.3 Hz) 1 H), 7.12 (M, 2 H), 5.41 (s, 2 H); MS: (M+H m/z = 106557.doc -57- 1312682 280.2) 〇Preparation 3 Ν-methoxy-oxime-methyl-4-(quinolin-2-ylmethoxy)-benzamide In a solution of 4-(quinolin-2-ylmethoxy)-benzoic acid (25.98 g, 93 mm 〇le), 250 ml of sulfinium chloride was added to A. The reaction mixture was stirred for 3 hours and excess sulfinium chloride was removed in vacuo. The gas acid was dissolved in tetrahydrocide (450 ml) and triethylamine (5 〇ml, 4 eq) was slowly added. The 〇 N• dimethyl group was added to the amine gasified gas (27 g, 3 eq·) and the reaction was allowed to stand for 18 hours. The reaction mixture was placed in a rotary evaporator to remove the solvent, and was partitioned between 1N NaOH and methylene chloride, separated, dried over magnesium sulfate, filtered and concentrated. The crude product was filtered through EtOAc (EtOAc) elut elut elut elut elut elut elut elut elut J=8.7 Hz, 1 H) 8.06 (d, J=8.3 Hz, 1 H), 7.81 (d, J=8.3 Hz, 1H), 7.67 (m, 3 H), 7.63 (d, J = 8.3 Hz, 1 H), 7.52 (m, 1 H), 7.01 (m, 2 H), 5.39 (s, 2 H), 3.52 (s, 3 H) 3.31 (s, 2H); MS : (M+H m/ z = 323.2) ° Preparation 4 2-=Bipyridin-4-yl-l-[4-(quinoline-2-yloxy)-phenyl]-ethanone in diisopropyl hydrazide clock ( 1 〇M) in the tetrahydroanthracene solution in 〇. 4-Methylpyridine (7.5 5 ml, 5 eq.) was added dropwise under Nz. After 30 minutes, the anion was cooled to -78 °C. Dissolve N-methoxymethyl-4((indol-2-ylmethoxy)-benzoic acid amine (5. 〇, 15.5 mmole) in tetrahydrofuran in a separate round bottom flask (5. In 77 ml, 0.2 M) and cooled to -78 ° C in N 2 . 1.2 eq. of 4 -曱 106557.doc -58 - 1312682 base bite anion was added dropwise to the guanamine solution. After 45 minutes, add a 4-methylpyridine anion. After another 3 minutes, acetic acid (iv) ml) was added dropwise and the reaction was slowly warmed to ambient temperature. The solid product (acetate) was filtered and partitioned between saturated sodium bicarbonate and di-methane. The layers were separated, dried, dried and concentrated to give the title compound as a brown solid (4.41 g, 80%). iH NMR (4〇〇MHz, CDci3) § 8.52 (d, J=5.8 Hz, 2 H), 8.19 (d, J=8.7 Hz, 1 H), 8.07 (d, J=8.7 Hz, 1H), 7.93 (m, 2 H), 7.82 (d, J = 8.3 Hz, 1 H), 7.75 (m, 1 H), 7.61 (d, J = 8.3 Hz, 1 H), 7.54 (dt, J=7.9, l .〇Hz, 1 H), 7.23 (m, 2 H) 7.07 (m? 2H), 5.42 (s, 2H), 4.19 (s, 2H); MS: (M+H m/z=355_2). Preparation 5 3-Dimethylamino-2-(»pyridin-4-ylquinolin-2-yloxy)-phenylpropanone at 2-°pyridin-4-yl- 1-[4-(Quinoline-2-ylmethoxyethylidene ethyl ketone (4 〇g, 11.3 mmole) was added with dimethoxymethyl dimethylamine (1 〇 ml), and the reaction mixture was Heating under reflux for 1 hour. Concentration gave the title compound in quantitative yields which can be used in the next step. LC/MS: RT = 1.4 min, MS: (M+H m/z = 410.2) 〇 Example 1 2-[ 4-(4-"bipyridin-4-yl-2Η-»bisoxa-3-yl)-phenoxyindolyl]quinine in 3-dimethylamino-2-° ratio bite-4 Adding cultivating hydrate (3.3 3 g, 40.5 mmole) to a solution of 1-yl-1-[4-(indol-2-ylmethoxy)-phenyl]-propyl ketone (9.57 g, 27 mmole) in methanol The reaction mixture was heated to 1 hr-59-106557.doc 1312682. The solvent was evaporated to give a white solid. The solid was washed with water and diethyl ether. g) Crystallization to give 8.34 g of the title compound (82%). 4 NMR (400 MHz, DMSO) δ 8.41 (m, 3 Η), 8.16 (s, 1 Η), 7.97 (m, 2 Η), 7.86 ( s, 1 Η), 7.75 (t, J = 7.9 Hz, 1 H), 7.68 (d, J = 8.3 Hz, 1 H), 7.60 (t, J = 7.5 Hz, 1 H), 7.33 (m, 2 H), 7.18 (m , 2 H) 7.15 (d, J=8.3 Hz, 1H), 7.〇6 (d, J=8.3 Hz, 1H), 5.38 (s, 2H); MS : (M+H m/z=379.2) Example 2 2-[4-(2-Methyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline in 2-[-4-(4 Add methyl hydrazine (3.5 ml, 1.5 eq.) to a solution of pyridin-4-yl-2H-pyrazol-3-yl)-phenoxyindolyl]-quinoline (1.72 g) in EtOAc (20 mL) And concentrated sulfuric acid (〇. 1 ml). The reaction mixture was stirred at ambient temperature for 1 hour to evaporate the solvent. The reaction mixture was partitioned between methylene gas and saturated sodium hydrogencarbonate. Drying, filtration and concentration were carried out using sulphuric acid. EtOAc (EtOAc: EtOAc (EtOAc) J=5.4 Hz, 2 H), 8.21 (d, J=8.7 Hz, 1 H), 7.80 (d, J=8.3 Hz, 1H), 7.77 (s, 1 H), 7.66 (m, 3 H), 7.53 (m, 1H), 7.19 (d, J = 8.7 Hz, 2 H), 7.11 (d, J = 8.7 Hz, 2 H), 7.01 (d, J = 6.2 Hz, 2H) 5.40 (s, 2H), 3.69 (s, 3H); MS: (M+H m/z = 393.3) 0 Example 3 2-[4-(Bumethyl-4-. Bipyridin-4-yl-111-. Bisazo-3_yl)-phenoxyindenyl]_喧106557.doc -60- 1312682 Scared in 2-[-4-(4-»-pyridine-3-yl-2H-"Biazole- Methyl hydrazine (3 5 ml, 5 eq) and concentrated sulfuric acid (0.1 ml) were added to a solution of 3-yl)-phenoxymethyl]-quinoline (1.72 g) in ethanol (2 mL). The reaction mixture was stirred at ambient temperature for a few hours and the solvent was evaporated. The reaction mixture was partitioned between methylene chloride and saturated sodium cesium carbonate. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated. The title compound (the main isomer) was obtained as a crude oil (0.97 g, 56%; 4 NMR (400 MHz, CDC13) δ 8.44 (d, J = 5.0 Hz, 2 H), 8.17 (d, J = 8.7 Hz, 1 H), 8.05 (d, J = 8.3 Hz, 1H), 7.81 (d , J=7.9 Hz, 1 H), 7.70 (m, 1 H), 7.66 (d, J=8.7 Hz, 1H), 7.54 (s, 1H), 7.53 (m, 1H), 7.37 (d, J= 8.7 Hz, 2H) 7.15 (d, J=5.0, 2H), 7.00 (d, J=8.7Hz, 2H), 5.38 (s, 2H), 3.93 (s,3H); MS : (M+H m/ z=393.3). Example 4 2-[4-(2-Ethyl-4-acridin-4-yl-2H-0-biazole-3-yl)-phenoxymethyl]-quineline was prepared according to the procedure for the preparation of hM-d-methyl- 4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-indole but substituting ethyl hydrazine to afford the title compound. Η NMR (400 MHz, CDC13) δ 8.35 (bs, 2Η), 8.23 (d, J=8.3 Hz, 1 H), 8.08 (d, J = 8.3 Hz, 1 h), 7·85 (d, j= 7.4 Hz, 1H), 7 83 (s, ! H), 7.74 (m, 2 H), 7.57 (t, j = 7 9 Hz, 1H), 7 21 (d, J = 8 7 Hz, 2 H) , 7.14 (d, J = 9.1 Hz, 2 H), 7.04 (m, 2H) 5.42 (s, 2H), 4.03 (q, J = 7.5 Hz, 2H), 1.36 (t, J = 7 5 Hz, 3H MS: (M+H m/z = 407.3) ° I06557.doc •61 - 1312682 Example 5 2-[4-(l-ethyl-4-αpyridin-4-yl-1Η-α-pyrazole 3-[4-(1-methyl-4-pyridyl-1H-pyrazol-3-yl)-phenoxymethyl]- The procedure for quinoline, but substituted with ethyl hydrazine to provide the title compound.咕NMR (400 MHz, CDC13) δ 8.35 (bs, 2H), 8.19 (d, J = 8.3 Hz, 1 H), 8.07 (d, J = 9.1 Hz, 1 H), 7.82 (d, J = 7.9 Hz (1, H), 7.73 (d, J = 9.1 Hz, 2H), 7.21 (bs, 2 H), 7.01 (d, J = 8.7 Hz, 2H) 5.39 (s, 2H), 4.24 (q, J = 7.5 Hz, 2H), 1.56 (t, J = 7.5 Hz, 3H); MS: (M+H m/z = 407.3). ''flat 6 dimethyl-(2-{4-° than pyridine-4_yl_3_[4_(quinolin-2-ylmethoxy)-phenyl]-carbazol-1-yl}-B The base-amine is prepared according to the procedure of 2-[4_(1_methyl_4_11 than bite_4-base ratio σ3_yl)-phenoxyindenyl]-quinoline but with (2_fluorenyl) -Hexyl)-dimethyl-amine substituted to provide the title compound. 1H NMR (400 MHz, CDCl 〇 δ 8.44 (dd, J = 4.6, 1.7, Hz, 2 H), g. 18 (d, J = 8.3 Hz, 1 H), 8.06 (d, J = 8.3 Hz, 1H ), 7.82 (d, J=B.7 Hz, 1 H), 7.71 (m 2H), 7.55 (t, J=7.1 Hz, 1H), 7.38 (d, J=8 7 Hz> 2H), 7.15 ( d, J=6.2 Hz, 2H) 7.00 (d, J=8.7 Hz, 2H), 5.38 (s, 2H), 4.25 (t, J=6.6 Hz, 2H), 2.82 (t'J-6.6 Hz, 2H ), 2.28 (s, 6H); MS : (M+H m/z = 450_4). 7 dimethyl-(2-{4-° pyridine_4_yl_5_[4_(quinoline_2_)甲 methoxy) _ phenyl] ratio 106557.doc -62- 1312682 0 -1--1-yl}_ethyl)-amine according to the preparation of 2-[4-(1-methyl-4-pyridin-4-yl Procedure for the preparation of -1 Η-pyrazol-3-yl)-phenoxymethyl]-quinoline, but substituted with (2-indolyl-ethyl)-dimethyl-amine to afford the title compound. 1H NMR (400 MHz, CDC13) δ 8.35 (d, J=6.2 Hz, 2 H), 8.22 (d, J=8.3 Hz, 1 H), 8.08 (d, J=8.7 Hz, 1H), 7.85 (m, 2 H) , 7.73 (m 2H), 7.57 (t, J = 7.1 Hz, 1H), 7.23 (m, 2H), 7.17 (d, J = 9.1 Hz, 2H) 7.00 (d, J = 6.2 Hz, 2H), 5.42 (s, 2H), 4.05 (t, J = 6.6 Hz, 2H), 2.66 (t, J = 7.1 Hz, 2H), 2.10 (s, 6H); MS: (M+H m/z = 450.4). Example 8 2-{4-[-indolepyridin-4-yl- 2-(2,2,2-Trifluoro-ethyl)-2H-«pyrazol-3-yl]-phenoxyindolyl}-quinolin according to the preparation of 2-[4-(1-methyl-4) -»pyridin-4-yl-1H-pyrazol-3-yl)-phenoxyindenyl]-quinoline, but substituted with (2,2,2-trifluoro-ethyl)-indole The title compound is provided. MS: (M+H m/z = 461.2). Example 9 2-{4-[-"pyridin-4-yl-1-(2,2,2-trifluoro-ethyl) -111-°bazol-3-yl]-phenoxyindenyl}-quinoline in 2-[-4-(4-. 1,1,1 was added to the dimethylformamide solution (140 mL) of pyridine-4-yl-211-°boxazol-3-yl)-phenoxyindenyl]-quinoline (26.5 g). -Trifluoro-2-iodo-ethane (21 mL, 2.0 eq.) and cesium carbonate (68.3 g, 3 eq.) and the reaction mixture was heated at 60 °C for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc (EtOAc)EtOAc. Purification by flash chromatography, eluting with 5 EtOAc / EtOAc / EtOAc / EtOAc (EtOAc) Preparative HPLC was eluted with acetonitile/methanol (98:2) on a chiralpak AD column at a flow rate of 43 0 ml/min to provide free assay of the pure title compound 13.4 g ° !H NMR (400 MHz, CDC13) δ 8.45 (m, 2 Η), 8.16 (d, J=8.3 Hz, 1 H), 8.04 (d, J=8.3 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J=8.3 Hz, 1 H), 7.69 (m, 1 H), 7.64 (d, J=8.3 Hz, 1 H), 7.50 (m, 1H), 7.36 (d, J=8.7 Hz, 2 H), 7.14 (d, J =6.2 Hz, 2H), 6.98 (d, J=9.1 Hz, 2 H), 5.35 (s, 2H), 4.75 (q, J=8.3 Hz, 2 H); MS : (M+H m/z = 427.1). MS : (M+H m/z = 461.2).实4^0 卜{4-Pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazole-l-ylpropan-2-ol according to Preparation 2 -[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxyindolyl]-quinoline but with 1-mercapto-propan-2- Alcohol substitution to provide the title compound. 1H NMR (400 MHz, CDC13) δ 8.44 (bs, 2 H), 8.20 (d, J = 8.3 Hz, 1 H), 8.08 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 8.3 Hz , 1 H), 7.75 (m 2H), 7.67 (d, J=8.3 Hz, 1H), 7.56 (t, J=8.3 Hz, 1H), 7.36 (d, J=8.7 Hz, 2H) 7.30 (m, 2H), 7.03 (d, J=9.1 Hz, 2 H), 5.40 (s, 2H), 4.29 (m, 1H), 4.23 (m, 1H), 4.02 (m, 1H), 1.83 (m, 1H) , 1.28 (d, J=6.2 Hz, 3H); MS: (M+H m/z=437.2) 〇 封 11 11 11 - {4 -α than bite -4 - base -5 - [ 4 - (喧-2 _ methoxyl)-propenyl] _ n than sal -1 -yl}-propan-2-ol · According to the preparation of 2-[4-(1-methyl_4_pyridin-4-yl-1H -Pyrazol-3-yl)-phenoxy 106557.doc -64. 1312682 methyl-]-quinoline procedure but substituting 丨-mercapto-propan-2-ol to afford the title compound. 1H NMR (4〇〇MHz, CDC13) δ 8.37 (d, J=6.2 Hz, 2 H), 8.23 (d, J=8.7 Hz, 1 H), 8.08 (d, J=8.3 Hz, 1H), 7.84 (m, 2 H), 7.75 (m 2H), 7.57 (t, J = 6.6 Hz, 1H), 7.20 (d, J = 9.1 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H) 7.00 ( Dd, J=6.2, 1.7 Hz, 2H), 5.42 (s, 2H), 4_17 (m, 1H), 3.94 (m, 2H), 3.86 (m, 1H), 1.12 (d, J=6.6 Hz, 3H MS: (M+H m/z = 437.3). Example 12 2-[4-(2-Isopropylpyridin-4-yl-2H-«pyrazol-3-yl)-phenoxyindenyl]- 喧 依照 according to Preparation 2-[4-(1- Procedure for methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, but substituted with isopropyl hydrazine to afford the title compound. 1H NMR (400 MHz, CDC13) δ 8·33 (bs, 2 H), 8.24 (d, J = 8.3 Hz, 1 H), 8.08 (d, J = 8.3 Hz, 1H), 7.86 (s, 1H) 7.83 (m, 1 H), 7.72 (m 2H), 7.58 (t, J=7.9 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H), 7.15 (d, J=9.1 Hz, 2H) 7.04 (m, 2H), 5.43 (s, 2H), 4.31 (m, 1H), 1.43 (d, J = 6.6 Hz, 6H); MS: (M+H m/z = 421.2). Example 13 2-[4-(4-0 唆-4-yl-iso-1嗤-5-yl)-phenoxyindolyl]-喧 Lin will 2-0 than bit-4-yl-1-[ 4-(喧琳-2-ylmethoxy)-phenyl]-ethanone (200 mg, 0·56 mmole) in dimethoxymethyl-dimethylamine (1 ml) Heat for 1 hour and concentrate. The crude product was dissolved in methanol/water (3:1, 4 ml) and hydroxylamine hydrogen chloride (43 mg, 1.1 eq.). After 1 hour, acetic acid was added (〇·〇 16 ml) and the reaction was heated under reflux for 1 hour. Cool to the ring 106557.doc -65- 1312682 and pour into saturated sodium bicarbonate, extract with methylene chloride, dry with magnesium sulfate, filter and concentrate. Dissolved in a 5% methanol / 1% ammonium hydroxide / ethyl acetate 50% hexanes in a 25 s column to afford the title compound as a tan solid (94 mg, 45%). 4 NMR (400 MHz, CDC13) δ 8.59 (dd, J=6.2, 1.7 Hz, 2 H), 8.36 (s, 1H), 8-20 (d, J=8.3 Hz, 1H), 8.07 (d, J =8.7 Hz, 1 H), 7.82 (d, J=9.1 Hz, 1 H), 7.73 (dt, J=7.1, 1.7 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.54 (m , 3H), 7.28 (d, J = 4.2 Hz, 2H) 7.05 (d, J = 9.1, 2H), 5.40 (s, 2H); MS: (M+H m/z = 380.2). Example 14 2-[4-(5-Pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline 2-n-bipyridyl-4-yl-4-444-(quinoline-2· The benzyloxy)phenyl]ethanone (2 mg) was heated in dimethoxymethyl-dimethylamine (1 ml) for 1 hour under reflux and concentrated. The crude reaction mixture was dissolved in ethanol (3 ml) and hydrogenated nucleus (90 mg, 2 eq.). Sodium (40 mg) was added to 3 ml of ethanol in a separate flask and stirred for 1 min. Sodium ethoxylate solution was added to the reaction mixture and heated under reflux for 1 hour. The reaction mixture was concentrated and purified with EtOAc EtOAc EtOAc EtOAc EtOAc咕NMR (400 MHz, CDC13) δ 8.53 (m, 3 Η), 8.14 (d, J=8.7 Hz, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.79 (d, J=7.9 Hz, 1 H), 7.70 (m, 1 H), 7.58 (d, J=8.7 Hz, 1H), 7.50 (m, 1H), 7.33 (d, J=9.1 Hz, 2H) 7.10 (d, J=6.2, 2H), 6.91 (d, J = 9.1 Hz, 2H), 5.34 (s, 2H) 2.77 (s, 3H); MS: (M+H m/z = 391.2). 106557.doc • 66- 1312682 Example 1 5 2-[4-(2-Methyl-5-Ethylene-4-yl H-yl)-phenoxymethyl]-isin according to Preparation 2_[4-( 5-Button _4_Base·Blowing Ice Base) _Phenoxymethyl]• Porphyrin procedure was replaced with acetonitrile chloride to provide the title compound. 4 NMR (400 MHz, CDC13) δ 9.21 (s, lH), 8.63 (S, 1H), 8.58 (m, 2 H), 8.17 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 8.7 HZ,1H), 7.81 (d,J=8.3 Hz, 1 H), 7.70 (m,i H),7 6〇(d,J=8 3 Hz 1H), 7.52 (m, 1H), 7.37 (m , 2H) 7.15 (d, J=6.2, 2H), 6.93 (d! 1 J=9.1 Hz, 2H), 5.35 (s, 2H); MS: (M+H m/z = 405.2). Example 16 2·[4-(2-methyl-6-pyridin-4-yl·pyrazolo-n,5-a]pyrimidine-7-yl)-p-oxycarbonyl]-quinoline Aminoamino-2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)phenyl]-propenyl ketone (229 mg, 0.56 mmole) in ethanol (3 ml) A brigade bite (2 eq.) and 5·methyl-2H-pyrazol-3-ylamine (1 〇 8 mg, 2 eq) were added and > the reaction mixture was heated under reflux for 3 hours. The reaction mixture was cooled to EtOAc (EtOAc m. 4 NMR (400 MHz, CDC13) δ 8.51 (d, J=7_9 Hz, 2H), 8.46 (S, 1H), 8.30 (m, 1 H), 8.18 (m, 1H), 7.89 (d, J=8.3

Hz, 1H), 7.78 (m, 1 H), 7.71 (m, 1 H), 7·60 (m, 1H), 7.41 (d, J=8.7, 2H), 7·21 (m, 2H) 7.07 (d, J=8.7, 2H), 6.60 (s, ih), 5.50 (s, 2H) 2.48 (s, 3H); MS: (M+H m/z=444.2) 〇 Example 17 2-[4- (2-methyl-6-acridine_4_yl_[i,2,4]triazolo[1.5-a]pyrimidin-7-yl)_106557.doc -67· 1312682 phenoxymethyl] -Quinoline according to the preparation of 2-[4-(2-methyl-6-pyridin-4-yl-pyrazolo[l,5-a]pyrimidin-7-yl)-phenoxymethyl]-quinoline The procedure was followed by 5-methyl-2H-[1,2,4]-triazol-3-ylamine to afford the title compound. 4 NMR (400 MHz, CDC13) δ 8.75 (s, 1H), 8.55 (m, 2H), 8.21 (d, J = 8.3 Hz, 1 H), 8.06 (d, J = 7.5 Hz, 1H), 7.84 ( d, J=7.1 Hz, 1H), 7.73 (m, 1 H), 7.64 (d, J=8.3 Hz, 1 H), 7.55 (m, 1H), 7.42 (d, J=8.7, 2H), 7.08 (m, 4H), 5.39 (s, 2H) 2.60 (s, 3H); MS: (M+H m/z = 445.2). Preparation 6 2 -Tajing-4-yl- l-[4-(infrared-2-ylmethoxy)-phenyl]-ethanone according to the preparation of 2-"tb-pyridin-4-yl-1- Procedure for [4-(quinolin-2-ylmethoxy)-phenyl]-ethanone, but 4-methylpyridinium was replaced by 4-methylhydrazine to afford the title compound. 1H NMR (400 MHz, CDC13) δ 9.12 (d, J = 5.4 Hz, 1 H), 9.08 (d, J = 8.7 Hz, 2.1 H), 8.20 (d, J = 8.3 Hz, 1H), 8.07 (d , J=8.3 Hz, 1 H), 7.96 (m, 2 H), 7.83 (d, J=7.9 Hz, 1 H), 7.76 (m, 1 H), 7.62 (d, J=8.3 Hz, 1 H ), 7.55 (m, 1 H) 7.38 (dd, J=5.4, 2.5 Hz, 1H), 7.09 (m, 2H), 5.44 (s, 2H) 4.23 (s, 2H); MS : (M+H m /z=356.2). Preparation 7 3-Dimethylamino-2-indole-4-yl-l-[4-(quinolin-2-ylmethoxy)-phenyl]- propyl ketone according to Preparation 3 - _ The procedure of methylamino-2-pyr ratio -4-yl-1-[4-(喧琳-2-ylmethoxy)-phenyl]-propenyl ketone but with 2·嗒耕_4· Substituting _ι_[4_(Quinolin I06557.doc -68- 1312682-2-ylmethoxy)-phenyl]-ethanone to provide the title compound. Lc/MS: RT = 1.8 min, MS: (M+H m/z = 411.2). Example 18 2-[4-(4-Taft-4-yl-211-"bi--3-yl)-phenoxyindenyl]- _ _ _ _ according to the preparation of 2-[·4-(4-pyridine _4_yl-2H- °pyrazol-3-yl)-p-oxymethyl]-quinoline procedure but with 3-dimethylamino-2-indole-4-ylindene-2 Substituted by methoxy)-phenyl]-propyl ketone to provide the title compound as a white solid. 1H NMR (400 MHz, CDC13) δ 9.11 (s, 1 Η), 9.01 (d, J = 5.0 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1 H), 8.25 (d, J = 8.7 Hz, (1), 7.89 (m 2H), 7.81 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7, 2H), 5.49 (s, 2H); MS: (M+H m/z = 380.2). Example 19 2-[4-(l-Methyl-4-indole-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolin according to Preparation 2-[4-(1 - mercapto-4-pyridin-4-yl-1H-pyrazol-3-yl)-p-oxymethyl]-quinoline but with 3-dimethylamino-2-indole-4 Substituted 1-[4-(quinolin-2-ylindolyl)-phenyl]-propenyl ketone to afford the title compound as a white solid. 4 NMR (400 MHz, CDC13) δ 9.11 (d, J = 2.5 Hz, 1H), 8.96 (d, J = 5.4 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1 H), 8.06 (d, J=8.3 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.73 (t, J=7.1 Hz, 1 H), 7.67 (m, 2H), 7.55 (t, J=7.1 Hz, 1H ), 7.34 (d, J=9.1 Hz, 2H), 7.24 (m, 1H), 7.02 (d, J=6.6 Hz, 2H), 5.39 (s5 2H) 3_97 (s, 3H); MS : (M+ H m / z = 394.2). 106557.doc -69- 1312682 Example 20 2-[4-(2-Methyl-4-indolyl-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinolin Procedure for 2-[4-(1-indolyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxyindolyl]-quinoline but with 3-dimethylamino group- 2-Indigo-4-yl-1-[4-(quinolin-2-yloxy)-phenyl]-propenyl ketone was substituted to afford the title compound as a white solid. iH NMR (400 MHz, CDC13) δ 8.99 (d, J = 2.5 Hz, 1H), 8.90 (d, J = 5.4 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1 H), 8.08 (d, J=8.7 Hz, 1H), 7.89 (s, 1H), 7.85 (d, J=8.3 Hz, 1 H), 7.75 (t, J=7. 1Hz, 1 H), 7.70 (d, J=8.3 Hz , 1H), 7.57 (t, J=7.1 Hz, 1H), 7.21 (d, J=8.7 Hz, 2H), 7.15 (d, J=9.1 Hz, 2H), 7.11 (m, 1 H), 5.43 ( s, 2H) 3.73 (s, 3H); MS: (M+H m/z = 394.2) ° Example 21 2-[-4-(4-pyrimidine-4yl-2H-pyrazol-3-yl)-benzene Oxymethyl]-quinoline according to the procedure for preparing 2-[-4-(4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxyindolyl]-quinoline and carrying out the necessary Chemically substituted to provide the title compound as a white solid. LC/MS: RT = 1.8 min, MS: (M+H m/z = 380.2). Example 22 2-[4-(4-indole-3-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinolin according to the preparation of 2-[-4-(4-pyridine-4 Procedure for the -2H-° ratio of β-yl-3-yl)-phenoxymethyl]-quinoline and the necessary chemical substitutions afforded the title compound as a white solid. LC/MS: RT = 1_7 min, MS: (M+H m/z = 380.2). Preparation 8 106557.doc • 70- 1312682 2- (3-Methyl-isoxazol-5-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethyl Preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 3,5-dimethylisoxazole for 4-methyl Pyridine to provide the title compound. LC/MS: RT = 2.3 min, MS: (M+H m/z = 359.2). Preparation 9 3-Dimethylamino-2-(3-indolyl-iso-β-azol-5-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]- Acryl ketone according to the procedure for preparing 3-dimethylamino-2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenyl ketone 2-(3-Methyl-isoxazol-5-yl)-1-[4-(indolyl-2-ylmethoxy)-phenyl]-ethyl-substituted to afford the title compound. LC/MS: RT = 2.1 min, MS: (M+H m/z = 414.2). Example 23 2-{4-[4-(3-Methyl-isoxazol-5-yl)-2H-pyrazol-3-yl]-phenoxymethyl}-quinolin according to the preparation 2-[- Procedure for 4-(4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxyindenyl]-quinoline but with 3-dimethylamino-2-(3-methyl- Isoxazol-5-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenyl ketone is substituted to provide the title compound. 4 NMR (400 MHz, CDC13) δ 8.23 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.94 (s, 1 H), 7.84 (d, J = 7.1 Hz, 1H), 7.74 (m, 1H), 7.69 (d, J=8.3 Hz, 1 H), 7.57 (t, J=6.6 Hz, 2 H), 7.46 (d, J=8.7 Hz, 2H), 7.08 ( d, J = 8.7 Hz, 2H), 5.88 (s, 1H), 5.42 (s, 2H), 2.23 (s, 3H); MS: (M+H m/z = 383.2). Example 24 106557.doc -71 - 1312682 2-{4-[2-Mercapto-4-(3-methyl A s „in T-isoxazole-5-yl)-2H-pyrazol-3-yl] -Phenoxymethylbuquinoline according to the preparation of 2-[4-( 1 _A | λ -4- -4- -4- -4- -4-yl-1 Η - 〇 -3- -3-yl) phenoxy fluorenyl a procedure for quinoline, but substituted with 3-dimethylamino-2-(3-methyl-isoxazol-5-yl)methoxy)phenyl]-propionyl ketone to provide the title White ruthenium solid of the compound. 1H NMR (400 MHz, CDC13) δ 8.25 (d, J = 8.7 Ηζ, in) 7_85 (d, J = 8.3 Hz, ijj) 7.28 (s, 1 H), 7.26 (d) 2H ), 5.45 (s, 2H), 3.7l = 397.2).

δ·12 (d, J=8.3 Hz, 1H), 7.89 (s, 1 H), 7-74 (m, 2H), 7.57 (t, 1=7.1 Hz, 1 H), J=10.4 Hz, 2H), 7.16 (d, J=8.7 Hz, (s, 3H), 2.16 (s, 3H); MS: (M+H m/z Example 25 2-{4-[l-mercapto-4-( 3-methyl s „ T-vola-iso-azazole-5-yl hlH·'»pyrazol-3-yl]-phenoxymethyl}-喧琳 according to the preparation of 2-[4-(K-Α Λ τ τ Violent pyridine _4_yl-1-pyrazole _3_yl) phenoxy A • dimethylamino 2·(3_methyl·iso 4 oxi) [4 (啥淋2-基methoxy) Phenyl]propenyl ketone is substituted to provide the title compound as a white solid. °H. 1H NMR (400 MHz, CDC13) δ δ·18 (d, J = 8.3 Hz, 1H) r VIII 8. 〇 7 ( d, J = 8.7 Hz, 1H), 7.81 (d, J = 7.1

Hz« 1 H), 7.77 (s, 1H) 7 7/f Λ?4 (t, J=7.1 Hz, 1H), 7.67 (d, J=8.7

Hz» 1 H), 7.54 (t, J=7 iu , L Hz, 1H), 7.48 (d, 8.7 Hz, 2 H), 7.07 (d, J=8.7 Hz, 2H), 5 81 , A (s , 1H), 5.41 (s, 2H), 3.92 (s, 3H), 2-20 (s, 3H); MS: (M+K, , m/z = 397.2). Example 26 106557.doc -72- 1312682 2-{4-[2-Methyl-5-(3-methyl-isoxazol-5-yl)-pyrimidin-4-yl]-phenoxymethyl} -啥琳 according to the procedure for the preparation of pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-porphyrin but with ruthenium chloride and 3-didecylamino-2-(3 - Mercapto-isoxazol-5-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenyl ketone substituted 'to provide the title compound as a hydrogenated hydrogen. 4 NMR (400 MHz, CDC13) δ 8.87 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1 H), 7.72 (t, J=7.1 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.53 t, J=6.6 Hz, 1 H), 7.45 (d, J=9.1 Hz, 2H) , 7.05 (d, J=9.1 Hz, 2H), 5.79 (s, 1H), 5.40 (s, 2H), 2.78 (s, 3H), 2.23 (s,3H); MS : (M+H m/z =409.2). Preparation 10 l-[4-(Quinoline-2-ylmethoxy)-phenyl]-ethanone was added to a solution of 2-chloromethylindole (2.5 g, 14 mmole) in acetone (47 ml) 4-hydroxy acetophenone (1.92 g, 1.0 eq.) and carbonic acid unloaded (2.5 g, 2 eq.). The reaction mixture was heated at 60 ° C for 16 h, cooled to EtOAc EtOAc (EtOAc) The phase layer was separated and the organic layer was dried using magnesium sulfate 'filtered and concentrated. The title compound was obtained as a white solid (2 75 g, 71%) eluting eluting eluting 1hnmr (400 MHz, CDC13) δ 8.19 (d, J=8.7 Hz, 1 H), 8.07 (d, J=8.7, 1H), 7_91 (m, 2H), 7.82 (dd, J=8.3, 1.3 1H) , 7.73 (t, J=7.i Hz, 1 H), 7.62 (d, J=8.3 Hz, 1 H), 7.54 (t, J=7.1 Hz, 1 H), 7-06 (m, 2H) , 5.42 (s, 2 H), 2.51 (s, 3 H); MS: (M+H m/z = I06557.doc -73- 1312682 278.3) ° Preparation 11 3-Dimercaptoaminoquinoline- 2-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone (1. 〇g, 3 61 mmole) at 2-methylmethoxy)-phenyl]-propenyl ketone The mixture was mixed with dimethoxymethyl-didecylamine (5 ml) and heated under reflux for 18 hours. The reaction mixture was cooled to RT and a tan precipitate formed. Filtered and washed with diethyl ether to afford title compound (840 mg, 71%). 1H NMR (400 MHz, CDC13) δ 8.39 (d, J = 8.3 Hz, 1 H), 7.97 (m, 2H), 7.91 (m, 2H), 7.84 (m, 2H), 7.75 (t, J = 6.6 Hz, 1 H), 7.62 (m, 3H), 7.05 (d, J=8.7 Hz, 2 H), 5.77 (d, J= 12.0, 1H), 5.40 (s, 2 H), 3.07 (bs, 3 H), 2.84 (bs, 3H); MS: (M+H m/z = 333.3) o Example 27 2-[4-(2-"pyridin-4-yl-2H-ubazole-3- ))-phenoxyindenyl]•quinoline in 3-dimethylamino-i-[4-(quinolin-2-ylmethoxy)-phenyl]-propenyl hydrazino (46 mg) To the ethanol (0.7 ml) solution was added water (〇7), acetic acid (〇〇5 ml) and 4-pyridylhydrazine (25 mg, 1 eq.). The reaction mixture was heated at EtOAc (3 mL), EtOAc (EtOAc)EtOAc. The title compound was obtained as a tan solid (31 mg, 61%). lH nmr (4〇〇MHz, CDC13) δ 8.51 (bs, 2H), 8.24 (d, J=8.7 Hz, 1 H), 8.11 (d, 2H), 7.84 (d, J=8.3 Hz, 1H), 7.74 (m, 2H), 7.69 (d, J 8.7 Hz, 1 H), 7.58 (t, J=7.1, 1H), 7.32 (bs, 2H), 7.19 (d, 106557.doc • 74- 1312682 J= 6.6 Hz, 2 H), 7.04 (d, J= 6.6, 2H), 5.40 (s, 2 H), 6.45 (s, 1H), 5.42 (s, 2H); MS : (M+H m/z= 379.2). Example 28 2-[4-(3-Methyl-5-«pyridin-4-yl[1,2,4]triazol-4-yl)-phenoxymethyl]·quinoline in isonicotine To a solution of EtOAc (3. The reaction mixture was cooled to ambient temperature and concentrated. A solution of 4-(quinolin-2-ylmethoxy)-phenylamine (1.70 g) in acetic acid (30 ml) was added to the mixture, and the mixture was warmed to reflux for 3 hr and cooled to ambient. The reaction mixture was concentrated in a rotary evaporator and purified by EtOAc EtOAc (EtOAc) WNMR (400 MHz, CDC13) δ 8.51 (d, J = 6.2 Hz, 2H), 8.24 (d, J = 8.7 Hz, 1 H), 8.08 (d, J = 8.7, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.76 (t5 J=8.3 Hz, 1H), 7.67 (d, j=8.7 Hz, 1 H), 7.58 (t, J=7.1, 1H), 7.29 (d, J=6.2 Hz, 2 H), 7-17 (d, J= 9.1 Hz, 2H), 7.12 (d, J=9.1 Hz, 2 H), 5.43 (s, 2 H), 2.31 (s, 3H); MS : (M +H m/z = 394.3). Preparation 12 4-Hydroxy-N-methoxy-N-mercapto-benzamide according to the preparation of N-methoxy-N-mercapto-4-(quinolin-2-ylmethoxy) The procedure for benzylideneamine, but substituted with 4-phenoxybenzoic acid, affords the crystalline compound as the title compound. MS: (M+H m/z = 272.3). Preparation 13 106557.d〇, -75· 1312682 1-(4-Benzyloxy-phenyl)-2-»pyridin-4-yl-ethanone according to the preparation of 2-pyridin-4-yl-1-[ Procedure for 4-(quinolin-2-ylmethoxy)-phenyl]-acetamidine but substituted with 4-benzyloxy-N-methoxy-N-methyl-benzamide to provide the title compound . MS: (M+H m/z = 304.2). Preparation 14 4-[3-(4-'oxy-phenyl)-i-methyl than sal-4_yl]-d is also prepared according to the preparation of 2-[4-(1-indolyl-4-pyridine ·4_yl-lH-oxazol-3-yl)-phenoxyindenyl]-quinoline but with 1-(4-hydroxy-phenyl)_2-pyridin-4-yl-B The ketone is substituted to provide the title compound. MS: (M+H m/z = 342.2). Preparation 15 4-(1-Methyl-4-0-Bite-4-yl-1H-0-pyran-3-yl)- in 4-[3-(4.benzyloxy-phenyl)_ι To a part bottle, palladium hydroxide (500 mg) was added to a solution of acetonitrile (1.28 g) in ethanol (50 ml) / ethyl acetate (50 ml). Add 4 psi to the pasteurizer and shake for 6 hours. The reaction mixture was filtered and concentrated. The title compound (860 mg, 91%) was obtained by EtOAc (m. 4 NMR (400 MHz, DMSO) δ 9.53 (s, 1H), Β.39 (d, J = 5.8 Hz, 2 H), 7.15 (m, 4H), 6.72 (d, J = 8.7 Hz, 1H), 3.84 (s, 3H); MS: (M+H m/z = 252.2). Example 29 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxyindolyl]-quinoxaline in 4-(1-methyl- 4-ntb-decyl-4-yl-111-0-p--3-yl)--(50 mg) of a 2-alkane (2 ml) solution of tris-phenylphosphine (84 mg), quinoxaline Benz-2-yl-nonanol 106557.doc -76- 1312682 (48 mg) and di-tertiary-butyl-aza-dicarboxylate (73 mg) and the reaction mixture was heated at 60 ° C for 18 hours . The reaction mixture was poured into in NaOH, extracted three times with methylene chloride, dried over magnesium sulfate, filtered and concentrated. Purification by MPLC Biotage chromatography gave the title compound (54 mg, 67 EtOAc). 1η NMR (400 MHz, CDC13) δ 9.09 (s, 1H), 8.45 (d, J = 6.2 Hz, 2H), 8.10 (m, 2 H), 7.77 (m, 2H), 7.55 (s, 1H), 7.37 (d, J=9.1Hz, 2H), 7.10 (d, J=6.9 Hz, 2 H), 7.01 (d, J=8.7, 2H), 5.41 (s, 2 H), 3.94 (s, 3H) ; MS : (M+H m/z = 394.4) ° Example 30 7 -Chloro-2 -[4-(1-methyl-4-0-Bite-4-yl-1H-0 than Sal-3) )-phenoxymethyl]-fluorene hydrogen chloride according to the procedure for preparing 4-(quinolin-2-yloxy)-benzoic acid methyl ester but with 4-(1-methyl-4-D ratio bite- 4-Base-1H-0 is substituted with indole-3-yl)- and 7-chloro-2-chloromethyl-quinoline to provide the title compound. 1H NMR (400 MHz, DMSO) δ 8.66 (d, J = 6.6 Hz, 2H), 8.54 (s, 1 H), 8.47 (d, J = 8.3, 2H), 8.04 (m, 2H), 7.70 (m, 2H), 7.65 (m, 1H), 7.36 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.7, 2H), 5.38 (s, 2H), 3.90 (s, 3 H); MS : (M+H m/z = 427.1). Example 3 1 6-Fluoro-2-[4-(l-fluorenyl-4-acridin-4-yl-1H-«pyrazol-3-yl)-phenoxymethyl]-quinoline hydrogen chloride Procedure for preparing 7-rat·2-[4_(ι_methyl_4_π ratio _4_yl-1H-0 to sal _3_yl)_phenoxymethyl]-quinoline hydrogen chloride However, 106557.doc -77 - 1312682 generation was taken as 2-chloromethyl-6-fluoro-quinoline to provide the title compound. iHNmr (400 MHz, DMSO) S8.67 (d, J = 6.6 Hz, 2H), 8.55 (s, 1 H), 8.42 (d, J = 8.3, 1H), 8.04 (m, 1H), 7.82 (m , 1H), 7.71 (m, 4H), 7.36 (d, J=8.7 Hz, 2H), 7.12 J-8.7, 2H), 5.37 (s, 2H), 3.91 (s, 3 H); MS : (M +H m/z = 411.2). Preparation 16 3'Fluoro-4-(quinolin-2-ylmethoxy)-benzoic acid quinoline-2-ylmethyl ester The following procedure was used to prepare 4-(quinolinylmethoxy)-benzoic acid methyl ester Instead of 3-vapor-4-yl-benzopyrene, the title compound was provided. Ms : (M+Hm/z = 439.0) oxime preparation 17 3-fluoro- 4-(quinolin-2-ylmethoxy)-benzoic acid according to the preparation of 4-(quinolin-2-ylmethoxy) - Procedure for benzoic acid but substituted with 3-fluoro-4-(indolyl-2-ylmethoxy)-benzoic acid quinoline-2-ylmethyl ester to provide the title compound. MS: (M+H m/z = 298.2). Preparation 18 3-Fluoro-N-decyloxymethyl-4-(quinolin-2-ylmethoxy)-benzoguanamine according to the preparation of N-methoxy_N-methyl-4-(quin Procedure for the phenanthroline-2-ylmethoxy)-benzamide to be substituted with 3-fluoro-4-(quinolin-2-ylmethoxy)-benzoic acid to afford the title compound. MS: (M+H m/z = 341.2). Preparation 19 ^[3-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl]_2•pyridine-4-yl-ethanone according to the preparation of 2-pyridin-4-yl-1-[4 -(Quinolin-2-ylmethoxy)-phenyl]-ethanone procedure but with 3-fluoro-N-methoxy-N-mercapto-4-(quinolin-2-ylmethoxy 106557 .doc -78- 1312682 base)-benzamide substituted to provide the title compound. Ms : (m+h _ 373.1). Example 32 2_[2_Fluorine_4-(4" than biting_4_yl]Η_π than wow_3_ylphenoxymethyl]-porphyrin according to Preparation 2 small 4_(4_〇比pyridine_4· Based on the procedure of "Bizozolidine"-phenoxymethyl]-(iv) but substituted by 叩+心(啥琳_2_ylmethoxy)_phenyl b-2-pyridin-4-yl-ethanone To provide the title compound. 咕nmr (Chi MHz, CDCI3) δ 8.47 (bs, 2Η), 8.19 (d, J=8.7 Hz, 1H), 8.05 (d, J-8.3 Hz, 1 H), 7.71 (m , 4H), 7.54 (t, J = 7.1 Hz, 1H), 7.18 (m, 3H), 7.07 (m, 2 H), 5.42 (s, 2 H); MS : (M+H m/z = 397.0 ° Example 33 2-[2-Fluoro-4-(1-methyl_4_0-pyridyl_4_yl_ih_〇bazole_3_yl)-phenoxymethyl]-喧琳

According to the procedure for the preparation of 2-[4-(1-methyl'4-»-Bite-4-yl-1H.-specific s--3-yl)-p-oxymethyl]-quinoline but with W3-fluoro- 4-(Quinolin-2-ylmethoxy)-phenyl]2 is substituted for the 4-amino group to give the title compound. 4 nMR J=6.2 Hz, 2H), 8.21 (d, J=8.3 1 H), 7.83 (d, J=7.9 Hz, 2H), (400 MHz, CDC13) δ 8.47 (d, Hz, 1H), 8.05 (d, J=8.7 Hz 7.72 (m, 2H), 7.55 (m, 2H), ηΛ6 (ηι? 2 H), 7.07 (m, 1H), 6.99 (m' 2H)' 5.45 (s, 2 H) , MS: (M+H m/z = 411.0). Preparation 20 2'3-fluoroquinolin-2-ylmethoxy)-benzoic acid quinolin-2-ylmethyl ester Substituting the procedure for the preparation of methyl 4-(phospho-2-ylmethoxybenzoate but substituting 106557.doc • 79· 1312682 2,3-difluoro-4-hydroxy-benzoic acid to provide the title compound. : (M+H m/z = 457 · 1) Preparation 21 2.3-Difluoro-4-(quinolin-2-ylmethoxy)-cracked acid according to the preparation of 4-(quinolin-2-yl) The procedure for methoxy)-benzoic acid is substituted with 2,3-difluoro-4-(quinolin-2-ylmethoxy)-benzoic acid quinolin-2-ylmethyl ester to afford the title compound. : (M+H m/z = 316.1) Preparation 22 2.3-Difluoro-N-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzoguanamine Procedure for the preparation of N-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide, but with 2,3-difluoro-4-(quinolin-2-yl) Methoxy)-benzoic acid To provide the title compound. MS: (M+H m/z=359.1). Preparation 23 1-[2,3-difluoro-4-(quinolin-2-ylmethoxy)phenyl] Pyridyl-4-yl-ethanone according to the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-yloxy)phenyl]-ethanone but with 2,3-di Fluoro-indole-methoxy-[upsilon]-methyl_4_(quinolin-2-ylmethoxy)-benzamide was substituted to give the title compound. MS: (?+? m/z=391.1). Example 34 2-[2,3-Difluoro-4-(1-indolyl-4-pyridin-4-yl-iH-n-pyrazol-3-yl)-phenoxymethyl]-quinoline

According to the procedure for preparing 2-[4-(1-methyl-4-» 比 _4_yl-1Η-π*.sodium-3-yl)-phenoxymethyl]-indole, but 1- [2,3-Difluoro-4-(indolyl-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethyl-substituted to afford the title compound. tHNMR 106557.doc -80 - 1312682 (400 MHz, CDC13) δ 8.44 (bs, 2H), 8.22 (d, J=8.7 Hz, 1H), 8.06 (d, J=8.7 Hz, 1 H), 7.84 (d , J=7.9 Hz, 1H), 7.70 (m, 2 H), 7.66 (s, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.08 (m, 3H), 6.88 (m,1H), 5.48 (s, 2 H); MS: (M+H m/z = 429.1). Preparation 24 2-Fluoro-4-(quinolin-2-ylmethoxy)-benzoic acid sulfin-2-ylmethyl ester according to the preparation of 4-(indolyl-2-ylmethoxy)-benzoic acid The ester procedure is substituted with 2-> fluoro-4-hydroxy-benzoic acid to provide the title compound. MS: (M+H m/z =439.0) ° Preparation 25 2-fluoro-4-(quinolin-2-ylmethoxyl)-benzoic acid according to the preparation of 4-(quinolin-2-ylmethoxy) The procedure for the benzoic acid was substituted with 2-fluoro-4-(salin-2-ylmethoxy)-benzoic acid-2-ylmethyl ester to afford the title compound. MS: (M+H m/z = 298.2). Preparation 26 _ 2-Fluoro-n-methoxymethyl-4-(quinolin-2-ylmethoxy)-benzimidamide according to the preparation of N-methoxy-N-methyl-4-( Procedure for quinoline-2-ylmethoxy)-phenylguanamine, but substituted with 2-fluoro-4.(quinolin-2-ylmethoxyl)-benzoic acid to afford the title compound. MS: (M+H m/z = 341.2). Preparation 27 {2-Fluoro-4-(quinolin-2-ylmethoxy)-phenylpyridin-4-yl-ethanone according to the preparation of 2-pyridin-4-yl-indole-[4-(quin Procedure for oxa-2-ylmethoxy)-phenyl]-ethanone but with 2-fluoro-n-methoxymethyl-4-(quinolin-2-ylmethoxy)-benzamide Substituted to provide the title compound. MS: (M+H m/z = 106557.doc - 81 · 1312682 373.0). Example 35 2-[3-Fluoro-4-(4-pyridin-4-yl-1H-indazole·3_yl)-p-oxymethyl]-quinoline according to the preparation 2-[-4-(4- ° than the bite-4 -yl-2Η·η than spyryl)-phenoxymethyl]-quinoline but with i-{2-fluoro-4-(quinolin-2-ylmethoxy)_ Phenyl}_2_pyridin-4-yl-ethanone is substituted to provide the title compound. Lfi nmr (4〇〇MHz, CDCI3) δ 8.47 (d, J=6.5 Hz, 2H), 8.22 (d, J=8.3 Hz, φ 1H)> 8.08 (d, J=8.7 Hz, 1 H), 7.84 (s, 1H), 7.82 (m, 1H), 7.74 (m, 1H), 7.65 (d, J = 8.7 Hz, 1 H), 7.55 (m, ih), 7.25 (m, 1 H), 7 ·18 (d, J=6.2 Hz, 2H), 6.85 (d, J=l〇_9, 2 H), 5.38 (s, 2 H); MS: (M+H m/z=397.2) 〇Preparation 28 4-(quinolin-2-ylmethoxy)-benzaldehyde was prepared according to the procedure for the preparation of methyl 4-(quinolin-2-ylmethoxy)-benzoate but substituted with 4-hydroxy-benzaldehyde The title compound ^ MS : (M+H m/z = 264.2). Preparation 29 1-Pyridin-4-yl-2-[4-(quinolin-2-ylindoleoxy)-phenyl]-ethanone in 4-acridinaldehyde (10.8 g) 2-propanol ( 50 ml) aniline (9.3 g) was added to the solution. After 15 minutes, the phenyl-pyridin-4-ylidene-amine product (68 〇/〇) was filtered and the crude product was used. Diphenyl phosphite (13.1 ml) was added to a solution of the imine in ethanol (3 5 ml) and stirred for 1 hour. Diethyl ether (2 mL) was added and (phenylaminopyrimidin-4-yl-methyl-phosphonic acid diphenyl ester (5.06 g) was filtered. EtOAc (0.98 g) Ml) The solution was stirred at -4 (TC N2, 106557.doc • 82 - 1312682. KOH/methanol (0.146 g/ΙΟ%) was added and then 4_(quinolin-2-yloxy)-benzaldehyde was added. The mixture was warmed to ambient temperature for 1 h and concentrated. EtOAc was evaporated from EtOAc EtOAc. The extraction was dried over magnesium sulphate, filtered and concentrated, purified by MPLC, to afford title compound. MS: (M+H m/z=355·1). Example 36 2-[4- (5-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline 1-pyridin-4-yl-2-[4-(quinolin-2-yl-methyl) Oxy)-phenyl]ethanone (168 mg) was heated in diethoxydecyl-dimethylamine (1 mi in reflux for 2 h. The reaction mixture was concentrated and dissolved in methanol (1 ml) Hydrate (0.023 ml) was added and the reaction mixture was heated at 65 T: 1 hour The reaction mixture was concentrated and purified using EtOAc EtOAc (EtOAc) elute elute elut 8.7 Hz, 1 H), 7.99 (d, J=8.7 Hz, 1H), 7.78 (d, J=8.3 Hz, 1 H), 7.66 (m, 2 H), 7.54 (s, 1 H), 7.48 ( m, 1 H), 7.36 (m, 2 H), 7.11 (d, J=7.1 Hz, 2H), 6.94 (d, J=8.3 Hz, 2H), 5.29 (s, 2H); MS : (M+ H m/z = 379.2). Example 37 2-[4-(1-Methyl-5-»pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-porphyrin According to the procedure for preparing 2-[4-(5- ° ratio -4-yl-1H- ° ratio), phenoxymethyl]-quinoline, but substituted with methyl hydrazine to provide The title compound and 106557.doc -83- 1312682 2-[4-(l-methyl-3·indolyl-4-yl-1Η-»bazol-4-yl)-phenoxyindenyl]-啥1H NMR (400 MHz, CDC13) δ 8.66 (bs, 2 Η), 8. Π (d J=8.7 Hz, 1H), 8.05 (d, J=7_9 Hz, 1 H), 7·81 (d , J=8.3 Hz 1H), 7.70 (m, 1 H), 7.63 (m, 2 H), 7.53 (t, J=7.1 Hz, 1 H) 7.21 (m, 2 H), 7.03 (d, J= 9.1 Hz, 2H), 6.89 (d, J = 8.7 Hz 2H), 5.32 (s, 2H), 3_80 (s, 3 H); MS: (M+H m/z = 393.2). Example 38 2-[4-(l-Methyl-3-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl quinazoline according to the preparation of 2-[4-(5-pyridine Procedure for 4--4-indolyl-pyrazol-4-yl)-phenoxymethyl]-quinoline, but substituted with methylhydrazine to provide the title compound and 2-[4-(1-indolyl-4) - Pyridin-4-yl-1 Η-pyrazol-4-yl)-phenoxyindenyl]•• porphyrin. 1H NMR (400 MHz, CDC13) δ 8_49 (bs, 2 Η), 8.20 (d, J = 8.3 Hz, 1 H), 8.07 (d, J = 8.3 Hz, 1 H), 7.83 (d, J = 8.3 Hz, 1H), 7.74 (m, 2 H), 7.55 (t, J=7.1 Hz, 1 H), 7.42 (m, 2H), 7.38 (s, 1H), 7.17 (d, J=8.7 Hz, 2H 7.00 (d, J=8.7 Hz, 2H), 5.38 (s, 2H), 3.95 (s, 3H); MS: (M+H m/z = 393.2).实#(〆• 2-Methylpyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl l·11-pyrazole-l-yl}-propan-2- The alcohol is prepared according to the procedure of 2·[4-(1-methyl_4_pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but with thiol_2_ Substituted with methyl-propan-2-ol to provide the title compound. NMR (400 MHz, CDC13) δ 8.47 (d,J=6·2

Hz, 2 H), 8.19 (d, j = s.7 Hz, 1 H), 8.07 (d, J=8.7 Hz, 1 H), 106557.doc -84- 1312682 7.82 (d, J = 7.9 Hz, 1H), 7.74 (t, J = 8.3 Hz, 1H), 7.68 (d, J=8.7 Hz, 1 H), 7.62 (s, 1H), 7.55 (t, J=7.1 Hz, 1 H), 7.39 ( d, J=8.7 Hz, 2H), 7.17 (m, 2H), 7.01 (d, J=8.7 Hz, 2H), 5.39 (s, 2H) 4.09 (s, 2H), 1.23 (s, 2H); MS : (M+H m/z=451_2). Example 丨 / 2-methyl-l-{4-pyridin-4-yl-5-[4·(quinolin-2-ylmethoxy)-phenyl]-pyrazole-l-yl}-propene- 2-alcohol according to the procedure for the preparation of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but with 1- Mercapto-2-mercapto-propan-2-ol was substituted to provide the title compound. 1H NMR (400 MHz, CDC13) δ 8.37 (d, J = 5.8 Hz, 2 H), 8.24 (d, J = 8.3 Hz, 1 H), 8.09 (d, J = 9.1 Hz, 1 H), 7.87 ( s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.76 (m, 1 H), 7.72 (m, 1H), 7.17 (m, 4 H), 7.00 (d, J=6.2 Hz, 2H ), 5.42 (s, 2H) 3.89 (s, 2H), 1.04 (s, 6H); MS: (M+H m/z = 451.2). Example ^4/(R)-l-{4-»Bistidin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-oxazol-1-yl} -2-ol according to the procedure for preparing 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxyindolyl]-quinoline but with (R Substituting 1-l-decyl-propan-2-ol to provide the title compound. 1H NMR (400 MHz, CDC13) δ 8.42 (m, 2 H), 8.18 (d, J = 8.3 Hz, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.81 (d, J = 8.3 Hz, 1H), 7.73 (m, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.61 (s, 1 H), 7.54 (m, 1H), 7.36 (d, J=9.1 Hz, 2 H ), 7.12 (m, 2H), 6.99 (d, J=8.7 Hz, 2H) 5.37 (s, 2H), 4.30 (m, 1H), 4.21 (dd, 106557.doc -85· 1312682 J=13.6, 2.5 Hz, 1H), 4.03 (dd, J = 13.6, 7.9 Hz, 1H), 1.26 (d, J = 6.2 Hz, 3H); MS: (M+H m/z = 437.2). Example & (8)-1-{4-Acridine-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazole-1-yl}-prop -2- drunk according to the preparation of 2-[4-(1•methyl_4_π than biting-heart group·]^-17 than spit-3-ylphenoxyindenyl]-quinoline but with (s) -l-decyl-propan-2-fermentation to provide the title compound. 4 NMR (400 MHz, CDC13) δ 8.42 (m, 2 H), 8.18 (d, J = 8.3 Hz, 1 H), 8.06 ( d, J=8.4 Hz, 1 H), 7.81 (d, J=8.3 Hz, 1H), 7.73 (m, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.61 (s, 1 H), 7.54 (m, 1H), 7.36 (d, 3=9.1 Hz, 2 H), 7.12 (m, 2H), 6.99 (d, J=8.7 Hz, 2H) 5.37 (s, 2H), 4.30 (m, 1H) ), 4.21 (dd, J=13.6, 2.5 Hz, 1H), 4.03 (dd, J-13.6, 7.9 Hz, 1H), 1.26 (d, J=6.2 Hz, 3H) ; MS : (M+H m/ z=437.2). Example 43 2-[4-(l-isopropyl·4_α-pyridyl_4_yl_丨^_pyrazole_3_yl)-phenoxymethyl]_ 啥琳 in 2- [4-(4-.Bistidin-4-yl-211-oxazol-3-yl)-phenoxymethyl]-quinoline (0.075 g) in dimethylformamide^1) Cesium carbonate (0.098 g) and 2-i〇do propane (0.030 ml) and the reaction mixture was heated at 60 ° C for 72 hours. The reaction mixture was poured into water and extracted with methylene gas. Purification by preparative TLC in 2% MeOH / 1% EtOAc /EtOAc /EtOAc iNMR (400 MHz, CDC13) 106557.doc -86- 1312682 δ 8.43 (d, J = 6.2 Hz, 2 H), 8.16 (d, J=8.7 Hz, 1 H), 8.05 (d, J=9.1 Hz, 1 H), 7.80 (d, J=8.3 Hz, 1H), 7.70 (m, 1H), 7.65 (d, J=8.7 Hz, 1 H), 7.59 (s, 1H), 7.53 (t, J=7.1 Hz, 1 H), 7.38 (d, J=9.1 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 5.38 (s, 2H) 4.51 ( m, 1H), 1.54 (d, J = 6.6 Hz, 6H); MS: (M+H m/z = 421.2) ° Example 44 2_[4-(l-isobutyl-4-°pyridin-4 -yl-1Η-»bisoxa-3-yl)-phenoxyindenyl]-quinolin according to the preparation of 2-[4-(1-isopropyl-4-pyridin-4-yl-1H-pyrazole- The procedure for 3-yl)-phenoxyindenyl]-quinoline was replaced with 1-iodo-2-methyl-propane to provide the title compound. 4 NMR (400 MHz, CDC13) δ 8.44 (m, 2H), 8.18 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1 H), 7.83 (d, J = 6.6 Hz, 1 H), 7.73 (t, J=6.6 Hz, 1H), 7.54 (s, 1H), 7.52 (m, 1H), 7.38 (d, J=9.1 Hz, 2 H), 7.15 (m, 2H), 7.00 (d, J=8.7 Hz, 2 H), 5.38 (s, 2H) 3.93 (d, J=7.5 Hz, 2 H), 4.29 (m, 1H), 0.95 (d, J=6.6 Hz, 6H) MS: (M+H m/z = 435.2). Example 45 2-[4-(l-Mercapto-4-°~ 咬-4-yl-1H-. 嗤-3-yl)-phenoxymethyl]-[1.8] mouth bite-

Add 3-phenyl in a solution of 4-(1-methyl-4-.indol-4-yl-1H-D than indol-3-yl)-pan (72 mg) in No. 17 (1.5 ml) Phosphine (121 mg), [1,8]non-2-yl-methanol (69 mg) and di-tertiary-butyl dicarboxylate (1 〇 6 mg) and the reaction mixture at 60 ° C Heat for 24 hours. The reaction mixture was poured into 1 n NaOH 106557.doc -87 - 1312682, extracted with methylene gas, dried over magnesium sulfate and concentrated. Via preparative TLC with 15% methanol / 70% ethyl acetate / 15 〇 /. Purify by hexane to afford the title compound (9.8 mg). NMR (400 MHz, CDC13) δ 9.13 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (d, J = 5.8 Hz, 2H), 8.23 (d, J = 8.3 Hz, 1 H), 7.21 (dd , J=8.5, 2.1 Hz, 1 H), 7.79 (d, J=8.7 Hz, 1H), 7.57 (s5 1H), 7.52 (m, 1H), 7.37 (d, J=9.1 Hz, 2 H), 7.16 (d, J=6.2 Hz, 2H), 7.01 (d, J=8.7 Hz, 2 H), 5.47 (s, 2H) 3.94 (s,3 H); MS : (M+H m/z=394.0 ). Preparation 30 Benzyl 4-(2-quinolin-2-yl-ethyl)benzoate in THF of 4-[diphenyl-phosphino]-methyl]benzoate (1.87 g) (16 ml) was added to sodium hydride (165 mg (60 〇/〇)) under N2 at 〇 °C. After 30 minutes, quinoline-2-carbaldehyde (0.50 g) was added and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was quenched with brine, extracted with chloroform, dried over magnesium sulfate, filtered and concentrated to afford crude. The crude product was placed in a solution of ethanol (15 ml) in a Babbitt shaker at 10 PSI H2 using palladium hydroxide (2 〇〇 mg) as a catalyst. At 4 minutes, the reaction mixture was filtered through celite and concentrated. 10-20 〇 / in Biotage MPLC chromatography. Ethyl acetate / hexane was dissolved to give the title compound. MS: (M+H m/z = 292.1). Preparation 31 4-(2-quinolin-2-yl-ethyl)-benzoic acid in the heart (2-quinolin-2-yl-ethyl)-benzoic acid methyl ester (680 mg) in hexanes (11 ml ) / methanol (3 ml) solution added! N-sodium hydroxide solution (4.67 Å. Ref. 106557.doc -88 - 1312682. The mixture was stirred for 4 hours and the pH was adjusted to 3. The white solid was dried to give the title compound (550 mg, 86%). (M+H m/z = 278.1). Preparation 32 N-decyloxy-N-methyl-4-(2-quinolin-2-yl-ethyl)-benzamide at 4-(2) -Methyl phenoxy-2-yl)-benzoic acid (530 mg) was added to a solution of 5 ml / acetonitrile in 5 ml of triethylamine (0.60 ml) and 0,N-dimethyl- Hydrogenation of the amine (240 mg). After 72 hours, the reaction mixture was poured into a solution of sodium hydroxide and extracted with a methylene chloride, dried over magnesium sulfate, filtered and concentrated. The title compound (516 1 ^, 88%) was obtained from 50% ethyl acetate. mp 8: (]^+11111/2 = 321.1). Preparation 33 2 · Pyridin-4-yl·1-[4 -(2-quinolin-2-yl-ethyl)-phenyl]-ethanone

According to the procedure for the preparation of 2-glyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone, but with Ν-methoxy-oxime-methyl-4 -(2-Quinolin-2-yl-ethyl)-benzamide was replaced to provide the title compound. MS: (M+Hm/z = 353.1). Example 46 2-{2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline at 2-°pyridin-4-yl- Add 3 ml of diethoxymethyl-didecyl-amine to l-[4-(2-quinolin-2-yl-ethyl)-phenyl]-ethanone (53 mg) and the reaction mixture 1 〇〇 °C for heating. After 3 hours, the reaction mixture was concentrated and decyl alcohol (3 ml) and hydr. The reaction mixture was heated at 60 ° C for 3 hours and concentrated. Purification by Biotage MPLC, eluting with 1-3% decyl alcohol / 0.5% saturated ammonium hydroxide in vacuo to afford title compound. 1H NMR 106557.doc • 89- 1312682 (400 MHz, CDC13) δ 8.47 (d, J=6.2 Hz, 2 H), 8.05 (d, J=8.3 Hz, 2 H), 7.80 (s, 1H), 7.78 (d, J=8.3 Hz, 2 H), 7.70 (t, J=7.1 Hz, 1H), 7.51 (t, J=7.1Hz, 1H), 7.32 (d, J=8.3 Hz! 2 H), 7.24 (m, 3H), 7.19 (d, J = 6.2 Hz, 2H), 3.31 (m, 2H), 3.22 (m, 2H); MS: (M+H m/z = 377.1). Example 47 2-{2-[4-(l-methyl-4-"Bite-4-yl·1Η-Bheptazole-3-yl)-phenyl]_6-yl}_quinoline

According to the procedure for preparing 2-{2-[4-(4-«pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethylbuquinoline, but with methyl hydrazine, Provide the title compound. lH NMR (400 MHz, CDC13) δ 8.45 (d, J = 6.2 Hz, 2 H), 8.06 (t, J = 10.4 Hz, 2 H), 7.77 (d, J = 7.1 Hz, 1 H), 7.70 ( t,j=8.3 Hz, 1 H), 7.57 (s' 1H), 7.50 (t, J=9.1 Hz, 1 H), 7.35 (d, J=8.3 Hz, 2H), 7.24 (m, 3H), 7.20 (d, J = 5. 〇 Hz, 2H), 3.97 (s 3H) 3.31 (m, 2H), 3_18 (m, 2H); MS (M+H 111/2 = 391.0) 〇 Preparation 34 2 -(2-chloro-heptan-4-yl)-l-[4-(quinolin-2-ylmethoxy)-phenylethanone according to the preparation of 2-pyridine-4-yl-1-[4- Procedure for (quinoline-2-yloxy)-phenyl]-ethanone but substituting 2-chloro-4-methylpyridine to afford the title compound. MS: (M+H m/z = 389.0). Example 48 2-(4-[4-(2-Chloropyridine-4-yl)-1Η-.Bizozole_3_yl]-phenoxyindolylquinoline_3'yl)-phenyl]-B According to the preparation of 2-{2-[4-(4-pyridine-4-yl-2-ii-pyridyl. Sit 106557.doc -90· 1312682 basal-paste procedure but with 2·(2-gas “bite·4 -Based by a small [4-(喧琳_2_yloxy)phenyl]-ethylidene-1 substitution to provide the title compound. 1hnmr (4〇〇MHz, CDC13) δ 8.23 (m, 2 Η) , 8.08 (d, J=8.7 Hz, 1 H), 7.83 (d, J=8.3 Hz, 1 H), 7.80 (s, 1H), 7.75 (t, J=7.1 Hz, 1 H), 7.67 (d , J=8.3 Hz, 1H), 7.57 (t5 J=7.1 Hz, 1 H), 7.33 (d, J=9.1 Hz, 2H), 7.05 (m, 4H), 5.40 (s, 2H); MS : ( M+H m/z = 413.1). Example 49 2-{4-[4-(2-Ga-pyridin-4-ylindenyl·1H•oxazolyl-3-yl)-phenoxyindenyl}- Quinline according to the procedure for preparing 2-{2-[4-(4-» ratio _4_yl-2Η-β than 嗤-3_yl)-phenyl]-ethyl}-quinoline肼 and 2_(2_qi_pyridine_4•yl)_1-[4_(quinolin-2-ylmethoxy)-phenyl]-ethanone were substituted to give the title compound. lH NMR (400 MHz, CDC13 ) δ 8.19 (m, 2 Η), 8.07 (d, J=8.3 Hz, 1 H), 7.83 (d, J=8.3 Hz, 1 H), 7.74 (t, J=8.3 Hz, 1H), 7.67 (d, J=8.3 Hz, 1 H), 7.58 (s, 1H), 7.55 (t, J=8.3 Hz, 1 H), 7.36 (d, J=8.7 Hz, 2H), 7.20 (s, 1H), 7.03 (m, 3H), 5.40 (s, 2H) 3.95 (s, 3H); MS: (M+H m/z = 427.0). Example 50 2-{4-[l- Methyl-4-(2-indolyl-pyridin-4-yl)-1Η-°pyrazol-3-yl]-phenoxymethyl bupene in 2-{4-[4-(2 Add a solution of -chloropyridin-4-yl)-1-methyl-1H-indazol-3-yl]-phenoxymethyl}-quinoline (100 mg) in dioxane (1.2 ml) Base ring ^^^(O.OGGmU'.^CpalladiumtetrakisXMmget^N^ sodium solution (0.234 ml). The reaction mixture was taken at 100. (: heating for 8 hours, 106557.doc • 91 · 1312682 Pour into 1 N NaOH, extract with a gas sample, dry with magnesium sulfate, filter and concentrate. Use 3% methanol/〇.5〇/0 in preparative TLC Dissolve in saturated ammonium hydroxide / 80% ethyl acetate in hexanes to provide the free base material. The product was stirred in ethyl acetate and 2 eq. succinic acid was added to give a white precipitate which was filtered. ' to provide the title compound as a white solid succinate (20 mg). A NMR (400 MHz, DMSO) δ 8.40 (d J = 8.3 Hz, 2 H), 8.25 (d, J = 5.0 Hz, 2 H), 8.07 (s, 1H), 8.00 (t, J=7.9 Hz, 2 H), 7.77 (t, J=6.6 Hz, 1 H), 7.67 (d, J=8.7 Hz, 2H), 7.60 (t, J =6.6 Hz, 1 H), 7.29 (d, J=9.1 Hz, 2H), 7.〇3 (m, 3 H), 6.92 (m, 1H), 5.35 (s, 2H), 3.85 (s, 3H ), 2.37 (s, 4H) 2.31 (s, 3H); MS: (M+H m/z = 407.0) 〇 Example 5 1 dimethyl-(4-{l-methyl-3-[4-( Quinoline-2-ylindolyl)-styl]_1H-pyrazol-4-yl}-° ratio -2-yl)-amine in 2-{4-[4-(2-gas-° ratio Dimethylmethyl hydrazide of pyridine-4-yl)-1-methyl-111-oxazol-3-yl]-phenoxymethyl}-quinoline (100 mg) ml) was added diethanolamine (0.035 ml) and the reaction mixture 13〇. The crucible was heated for 72 hours. The reaction mixture was poured into water and extracted with diethyl ether and dried over magnesium sulfate. Separate by preparative TLC using 6% ethyl acetate in hexanes to afford the free base of the title compound. The product was placed in ethyl acetate and stirred and 1 eq. succinic acid was added. After 18 hours, the white precipitate was filtered to afford succinate (24 mg). 4 NMR (400 MHz, DMSO) δ 8.40 (d, J = 8.3 Hz, 1 H), 8.03 (s, 1H), 7.98 (m, 2 H), 7.90 (d, J = 5.4 Hz, 1 H), 7.77 (m, 1H), 7.65 (d, J=8.3 Hz, 1 H), 106557.doc •92· 1312682 7.59 (m,1 Η), 7.31 (d,J=6.6 Hz,2H), 7·04 (d, J = 9.1 Hz, 2 H), 6.37 (m, 2 H), 5.35 (s, 2H), 3.84 (s, 3H), 2.80 (s, 6H) 2.37 (s, 4H); MS ·_ (M+H m/z = 436.0). Preparation 35 3-Dimethylamino-1-pyridin-4-yl-propenyl ketone Addition of n,N-dimethyl in I-0 to butyl-4-keto-ketone (1·62 g) The amine diacetaldehyde (10 ml) was brewed and the reaction mixture was at 120. (: heating for 2 hours and concentrating to give the title compound. MS: (M+H m/z=177.0). Preparation 36 4-[2-(4-benzyloxy-phenyl-2H-carbazole-3 -yl)-咐&gt; pyridine is added to a solution of 3-didecylamino-1-one to benzyl-4-yl-propyl ketone (590 mg) in methanol (10 ml). (4-benzyloxy-phenyl)-hydrazine hydrogen chloride (836 mg) and the reaction mixture was heated to 6 ° C for 6 hours. The reaction mixture was poured into saturated sodium hydrogen carbonate and extracted with ethyl acetate. The residue was purified by EtOAc (EtOAc) (EtOAc) Than a bite-4-yl-吼. sit-1 _yl)--in the 4-[2-(4-benzyloxy-phenyl-2H-° than indole-3-yl)-n ratio bite (610 mg Palladium hydroxide (20%, 343 mg) was added to a solution of ethyl acetate (15 ml) / ethanol (15 ml). The reaction mixture was placed in a Babbler shaker for 45 hours in 45 psi h2 gas. The reaction mixture was filtered through celite and concentrated. EtOAc (m.) / </ RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; -Metidazole-1 -yl)-phenoxymethyl]-quinoline is added to the solution of 4-(5-pyridin-4-yl-pyrazol-1-yl)phenol (82 mg) in acetone Potassium (153 mg) and 2-mercapto-quinoline (95 mg) and the reaction mixture was heated at 60 C for 18 h. The reaction mixture was poured into brine and extracted with ethyl acetate. Filtration and concentration. Purified by combiflash MPLC to provide the title compound (91). H NMR (400 MHz, CDC13) δ 8.51 (m, 2 Η), 8.20 (d, J = 8.7 Hz, 1 H), 8.06 (d, J=8.7 Hz, 1 H), 7.83 (d, J=7.1 Hz, 1H), 7.74 (m, 2H), 7.65 (d, J=8.7 Hz, 1 H), 7.57 (m, 1H), 7.20 (d, J=8.7 Hz, 2 H), 7.09 (d, J=5.8 Hz, 2H), 7.02 (d, J=9.1 Hz, 2H), 6.60 (d, J=1.7 Hz, 1H), 5.39 (s, 2H); MS: (M+H 79·0). Example 53 2-[4-(3-Methyl-5-pyridin-4-yl-pyrazol-1-yl)-phenoxymethyl]-quinoline according to the preparation of 2-[4-(5-pyridine- 4-(4-pyrazol-1-yl)-phenoxymethyl]-quinoline procedure but substituted with (1,1-dimethoxy-ethyl)-dimethyl-amine to provide the title compound . 4 NMR (400 MHz, CDC13) δ 8.49 (d, J = 6.2 Hz, 2 H), 8.20 (d, J = 8.3 Hz, 1 H), 8.06 (d, J = 8.7 Hz, 1 H), 7.83 ( d, J = 8.3 Hz, 1H), 7.74 (m, 1H), 7.64 (d, J = 8.3 Hz, 1 H), 7.54 (m, 1H), 7.18 (d, J = 8.7 Hz, 2 H), 7.07 (d, J=6.2 Hz, 2H), 7.00 (d, J=9.1 Hz, 2H), 6.40 (s, 1H), 5.38 (s, 2H), 2,35 (s,3H); MS : ( M+H m/z=393.4) 0 Preparation 3 8 J06557.doc -94- 1312682 3-Chloro-4-(quinolin-2-ylmethoxy)-benzoic acid methyl acetate according to the preparation of 4-(quinoline) The procedure for methyl 2-methylmethoxy)-benzoic acid was replaced with 3-chloro-4-hydroxy-benzoic acid to afford the title compound. MS: (M+H m/z = 328.0). Preparation 3 9 3-Chloro-4-(quinolin-2-ylmethoxy)-benzoic acid according to the procedure for the preparation of 4-(indolyl-2-ylmethoxy)-benzene. -4-(Saliva-2-yloxy)-benzoic acid methyl ester was substituted to provide the title compound. (M+H m/z = 314.0). Preparation 40 3-A-N-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzoguanamine according to the preparation of N-methoxy-N-methyl-4 The procedure for -(2-fluoren-2-yl-ethyl)-benzamide was replaced by 3-chloro-4-(quinolin-2-ylmethoxy)-benzoic acid to afford the title compound. (M+Hm/z=356.9). Preparation 41 1- [3-Ga-4-(indolyl-2-ylmethoxy)-phenyl]-2-° ratio biting _4_yl-ethanone according to the preparation of 2-pyridin-4-yl- Procedure for 1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but 3-methoxy-N-methoxy-N-methyl-4-(喧琳-2- Substituted by methoxy)-benzamide to give the title compound (M+Hm/z = 389.0). Example 54 2- [2-Ga-4-(4-» 比咬-4-yl-111-° than indol-3-yl)-phenoxyindenyl]-喧喧琳 according to Preparation 2-{2-[ 4-(4-0 than bite-4·-yl-2H-0 than salivation_3_yl)-phenyl]-ethyl}-啥琳's procedure but with 1-[3-chloro-4-(喧Lin-2-ylmethoxy)-phenyl]_2.pyridin-4-yl-ethanone is substituted to provide the title compound. NMR (400 106557.doc -95· 1312682 MHz, CD3OD) δ 8.37 (m, 4 Η), 8.02 (d, J=8.7 Hz, 2 H), 7.93 (d, J=8.3 Hz, 2H), 7.78 ( m, 2 H), 7.61 (t, J = 7.1 Hz, 1 H), 7.31 (m, 2H), 7.21 (m, 1 H), 5.44 (s, 2H); MS : (M+H m/z = 413.0). Example 55 2-[2-Chloro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-indole according to Preparation 2-{2 -[4-(4-«Bistidin-4-yl-2H-.pyrazol-3-yl)-phenyl]-ethyl}-quinoline but with methyl hydrazine and 1-[3-chloro -4-(Quinolin-2-ylindolyl)-phenyl]-2-pyridin-4-yl-ethanone was substituted to provide the title compound. 1Η NMR (400 MHz, CDC13) δ 8.47 (d, J = 6.2 Hz, 2 H), 8.21 (d, J = 8.3 Hz, 1 H), 8.04 (d, J = 7.5 Hz, 1H), 7.83 (d , J=8.3 Hz, 1 H), 7.78 (d, J=8.7 Hz, 1 H), 7.72 (m, 1H), 7.56 (m, 3 H), 7.21 (m, 1H), 7.14 (d, J = 6.2 Hz, 2 H), 6.97 (d, J = 8.7 Hz, 1 H), 5.46 (s, 2H), 3.95 (s, 3H); MS: (M+H m/z = 427.1). Preparation 42 4_(4-Pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenol in 4-methoxy-N-pyridin-4-yl-benzamide (75 mg) of P0C13 (3 ml) was added PC15 (68 mg) and the reaction mixture was heated at reflux for 5 hours. The reaction mixture was concentrated and dissolved in dimethylformamide (2 ml) and EtOAc (5 eq, 100 mg) was added and stirred for 2 hr. The reaction mixture was concentrated and diluted with isopropyl alcohol (3 mL) and added 〇_25 ml concentrated HCM. The reaction mixture was stirred for 18 h, quenched with EtOAc EtOAc EtOAc EtOAc. The crude product was dissolved in methylene chloride (2 mL) and boron tribromide (0··············· The reaction mixture was warmed to ambient temperature and stirred for 18 h. The reaction mixture was quenched with 1 ν NaOH and the pH was adjusted to 9 and extracted with di-methane to dryness, filtered and concentrated. Purified by </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; MS: (M+H m/z = 239.2). Example 56 2-[4-(4-.Bistidin-4-yl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-quinoline will be placed in a 7 ml 4-(4-β-But-4-yl-4Η-[1,2,4]triazol-3-yl)-phenol (44 mg) in dimethylformamide in a Teflon-capped bottle Solution (iml) Carbonate planer (185 mg) and 2·gasmethyl-quinoline (37 mg) were added and the reaction mixture was heated at 60 ° C for 18 hours on a shaker. The reaction mixture was poured into EtOAc (EtOAc m. 4 NMR (400 MHz, CDC13) δ 8.87 (s, 1H), 8.65 (d, J = 6.0 Hz, 2 H), 8.37 (d, J = 8.3 Hz, 1 H), 8.03 (d, J = 8.7 Hz , 1H), 7.94 (d, J=7.9 Hz, 1H), 7.78 (m, 1 H), 7.70 (d, J=8.3 Hz, 1 H), 7.61 (t, J=5.8 Hz, 1 H), 7.40 (m, 4H), 7.14 (d, J = 9.1 Hz, 2 H), 5.38 (s, 2H); MS: (M+H m/z = 380.2) ° Preparation 43 [4-(quinoline- 2-Chloromethoxy)-phenyl]-fluorene in 4-(啥-lin-2-ylmethoxy)-phenylamine (1.73 g) in 30 mL of concentrated HC1 suspension finally added at 0 ° C. Na (53 1 mg). After 3 hours, tin chlrodie (3.95 g) was dissolved in 20 mL of concentrated HCl and was slowly added dropwise to the mixture, and then the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was filtered and dried to give crystalljjjjjjjjj MS: (M+H m/z = 266.3). Example 57 2-[4_(5-°-pyridyl-4-yl-[1,2,4]triazol-1-yl)-phenoxyindenyl]-quinoline isonicotinium amide (4.15 g) The mixture was heated under reflux for 3 hours with 35 ml of n-dimethyl decylamine. The reaction mixture was cooled to ambient temperature and concentrated to give 5·02 g of N-monomethylaminomethylene-different to the amine. Add N-dimethylamido to a solution of [4-(啥琳-2-ylmethoxy)-phenyl]•肼 (3.16 g) in methanol (3 mL) and acetic acid (2.5 mL) The amide was reacted with decylamine (11() g) and the reaction mixture was heated under reflux for 72 hours. The reaction mixture was concentrated on EtOAc (EtOAc) elute 4 NMR (400 MHz, CDC13) δ 8.60 (d, J = 5.8 Hz, 2 H), 8.22 (d, J = 8.7 Hz, 1 H), 8.10 (s, 1H), 8.07 (d, J = 8.7 Hz , 1H), 7.85 (d, J=7.1 Hz, 1H), 7.76 (m, 1 H), 7.66 (d, J=8.3 Hz, 1 H), 7.56 (m, 1 H), 7.56 (m, 1H) ), 7.38 (d, J=6.2 Hz, 2 H), 7.26 (d, J=8.7Hz, 2H), 7.11 (d, J=9.1Hz, 2H), 5.42 (s, 2H); MS : (M +H m/z=380.3). Preparation 44 [4-(quinolin-2-ylmethoxy)-phenyl]-indole according to the procedure for the preparation of [4-(quinolin-2-ylmethoxy)-phenyl]-indole but with 4 -(Quinolin-2-ylmethoxy)-phenylamine in place of ' to provide the title compound. MS: (M+H m/z = 266_2). Example 58 106557.doc -98 - !312682 2-[4_(3 -Methyl to 0^_4_yl-[1,2,4]triin-1-yl)-phenoxymethyl]_quinoline According to the procedure for preparing 2-[4-(5-°Bite-4-yl-[1,2,4]tris-1-yl)-phenoxymethyl]-quinoline but with N,N- Dimethylacetamide dialdehyde was substituted to provide the title compound. 1H NMR (400 MHz, CDC13) δ 8.58 (d, J = 6.2 Hz, 2 Η), B.22 (d, J = 8.3 Hz, 1 H), 8.08 (d, J = 8.3 Hz, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.74 (m, 1 H), 7.65 (d, J=8.3 Hz, 1 H), 7.56 (m, 1 H), 7.36 (d, J=6.2 Hz, 2 H), 7.25 (d, J=9.1 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 5.41 (s, 2H), 2.48 (s, 3H); MS : (M+H m/z =394.4). Preparation 45 4-(Quinolin-2-ylmethoxy)-benzamide in one of 2-chloroindolyl-quinolin (1.57 g) and 4-hydroxy-benzoguanamine (995 mg) To a solution of the guanamine (20 mL) was added cesium carbonate (7.3 g) and the reaction mixture was taken to 80. Heat for 18 hours. The reaction mixture was poured into water and dried with EtOAc (EtOAc)EtOAc MS: (M+H m/z = 279.3). Example 59 2-[4-(2-Bistidyl-4-yltriazol-3-yl)-phenoxymethyl]quinoline according to the preparation of 2-[4-(5-acridin-4-yl-[ Procedure for 1,2,4]triazol-1-phenoxymethyl]-quinoline, but substituted with 4-(quinolin-2-yloxy)benzamide and pyridine 4 hydrazine, To provide the title compound. 1h (10)Mm, CDC13) δ 8.65 (d, J = 6.2 Hz, 2 H), 8.21 (d, J = 8.3 Hz, 1 H), 8-08 (s, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 106557.doc • 99· 1312682 7·73 (m,1 H), 7.65 (d, J=8.7 Hz, 1 H), 7.55 (m,1 η), 7.43 (d, J=9.1 Hz, 2H), 7.32 (d, J=6.2 Hz, 2 H), 7.05 (d, J=8.7Hz, 2H), 5.40 (s, 2H) MS: (M+H m/z = 380.2). Example 60 2-[4-(5-Methyl-2-°~Bite-4-yl-2H-[1,2,4]Tris--3-yl)-phenoxymethyl]-喧琳According to the procedure for preparing 2-[4-(5-pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline, but 4-(quinoline- 2-Methoxymethyl)-benzamide, 11 is substituted with butyl-4-yl-indole and N,N-dimethylacetamide dialdehyde to provide the title compound. 1H NMR (400 MHz, CDC13) δ 8.61 (d, Hz, 2 H) 8-21 (d, J = 8.7 Hz, 1 H), 8.07 (d, J = 7.9 Hz, 1H), 7.83 (d, J =8.3 Hz, 1H), 7.75 (m, 1 H)} 7.64 (d, J=8.3 Hz, 1 H), 7.55 (m,1 H), 7.56 (m,1H), 7.41 (d, J=9.1 Hz, 2 H), 7.29 (d, J = 6.2 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 5.40 (s, 2H), 2.47 (s, 3H); MS : (M+H m/z = 394.3). Preparation 46 4-[3-(4-Benzyloxy-phenyl)_1H-«bizozol-4-yl]-acridine at 1-(4-(milyl)-benzyl)-2 -π ratio σ Toluene (20 ml) and 1.6 g of diethoxymethyl-dimethyl-amine were added to a solution of 1,4-methyl-acetamidine (1.58 g), and the reaction mixture was heated under reflux for 1 hour. The reaction mixture was concentrated, dissolved in EtOAc (EtOAc) (EtOAc) The reaction mixture was concentrated and purified with EtOAc EtOAc EtOAc EtOAc MS: (M+H m/z = 328.1). 106557.doc • 100- 1312682 Preparation 47 4-[3-(4-Benzyloxy-phenyl)_1_(2,2,2-trifluoro-ethyl)_ll·l-»Bizozol-4-yl Adding carbonic acid to a solution of 4-[3-(4-f-oxyphenylpyrazole-4(yl)]_ σ pyridine (one of 42 g) in methyl decylamine (7 ml) Planing (0 65 g) and 1,1,1-trifluoro-2·iodo-ethane (〇·29 ml). The reaction mixture was heated at 6 ° C for 24 hours, poured into water and extracted with a gas. Three times. Purification by biotage MPLC chromatography eluting with EtOAc/EtOAc/EtOAc (EtOAc:EtOAc Preparation 48 4-[4-Pyridin-4-yl-i-(2,2,2-trifluoro-ethyl)_ih-pyrazol-3-yl]-phenol according to the preparation of 4-(1-methyl- Procedure for 4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol but with 4-[3-(4-benzyloxy-phenyl)_ι_(2,2,2-trifluoro-B Substituted by carbazol-4-yl]-pyridine to provide the title compound.ms: (M+H m/z = 320.1). Example 61 2-{4-[4-nt bite_4_yl_ι_(2 , 2,2-trifluoro-ethyl)-lH-° than indol-3-yl]-phenoxyindolyl}-quinoxaline in 4-[4-pyridyl-1-(2,2,2 -trifluoro-ethyl)-1Η-pyrazole_3_ Add phenylphenol (79 mg) and quinoxaline-2-yl-sterol (π mg) in dioxane (2) solution, adding triphenylphosphine (1〇5 mg) and diazocarboxylic acid -di-t-butyldiazacarboxalate (92 mg) and the reaction mixture was heated at 6 (rc). After 18 hours, the reaction mixture was poured into 1N Na〇n and extracted with methylene chloride. Drying with magnesium sulfate, filtration and concentration. Purify with MpLc 106557.doc -101 - 1312682 biotage, eluting with 2% methanol / 0.5% ammonium hydroxide / 60% ethyl acetate / hexanes to afford title compound Mg). 4 NMR (400 MHz, CDC13) δ 9.09 (s, 1 Η), 8.52 (m, 2 Η), 8.13 (m, lH), 8.10 (m, 1H), 7.79 (m, 2 H), 7.73 (s, 1 H), 7.40 (d, J=8.7, Hz, 2 H), 7-24 (m, 2H), 7.04 (d, J=8.7 Hz, 2 H), 5.32 (s, 2H), 4.79 (q, J = 8.3 Hz, 2 H); MS: (M+H m/z = 462.1). Example 62 8_Methoxy-2-[4-(l-methyl·4_indolepyrazol-3-yl)-phenoxyindenyl]-quinoline according to the preparation 2-{4-[4 -pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-111-pyridin-3-yl]-phenoxymethylbuquinoxaline procedure but with 4_(1_ Substituted fluorenyl-4-pyridin-4-yl-1H-indazol-3-yl)-phenol and decyloxy-quinolin-2-ylmethanol to afford the title compound. NMR (400 MHz, CDC13) δ 8.45 (d, J = 6.2 Hz, 2 H), 8.15 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7·55 (s , 1H), 7.44 (m, 1 H), 7.37 (m, 3 H), 7.15 (d, J = 5.8, Hz, 2 H), 7.07 (d, J = 7.5 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2 H), 5.46 (s, 2H), 4.08 (s, 3 H), 3.94 (s, 3H); MS: (M+H m/z = 423.1). Example 63 2-[4-(l-Mercapto-4-indolyl-4-yl-1H_nbiazole-3-yl)-phenoxyindenyl]_〇比 bite [l,2-a] spray Bite -4-_ according to the procedure for the preparation of 2-[4-(4-pyridine-4-yl-_411-[1,2,4]triazol-3-yl)-phenoxyindolyl]-喧The [i,2-a] mouth bite _4__ is substituted for the 2_ gas 曱 _σ ratio to provide the title compound. iHNMR (400 MHz, CDC13) δ 9.01 106557.doc •102- 1312682 (d, J=7.1 Hz, 1 H), 8.43 (m, 2H), 7.72 (m, 1H), 7.59 (d, J = 8.7 Hz) , 1H), 7.53 (s, 1H), 7.37 (d, J=9.1 Hz, 2H), 7.12 (m, 3H), 6.93 (d, J=8.7Hz, 2H), 6.68 (s, 1 H), 5.05 (s, 2H), 3.92 (s, 3H); MS · (M+H m/z = 410.1). Example 64 2-[4-(1-Methyl-4-n ratio _4_yl_1 Η-α ratio. Sodium-3-yl)-phenoxymethyl]-oxime according to Preparation 2-[4 -(4_Pyridin-4-yl-411-[1,2,4]triazol-3-yl)-phenoxyindolyl]•quinoline but with 2-chloromethyl-quinazoline instead To provide the title compound. 1H NMR (400 MHz, CDC13) δ 9.43 (s, 1H), 4.43 (d, J = 4.6 Hz, 2 H), 8.07 (d, J = 8.3 Hz, 1H), 7.93 (d, 2H), 7.69 ( t, J=7.9 Hz, 1H), 7.55 (s, 1 H), 7.36 (d, J=8.7 Hz, 2 H), 7.15 (d, J=6.2, Hz, 2 H), 7.05 (d, J = 8.7 Hz, 2H), 5.48 (s, 2H), 3.94 (s, 3H); MS: (M+H m/z = 394.2). Preparation 49 4-Benzyloxy-2-fluoro-benzoic acid benzyl ester according to the procedure for the preparation of methyl 4-(quinolin-2-ylmethoxy)-benzoate but with two equivalents of benzyl bromide and 2 -Fluoro-4-hydroxy-benzoic acid substitution to provide the title compound. MS: (M+H m/z = 337.2). Preparation 50 4-Benzyloxy-2-fluoro-benzoic acid according to the procedure for the preparation of 4-(quinolin-2-ylmethoxy)-benzoic acid but with 4-benzyloxy-2-fluoro-benzoic acid The benzyl ester was replaced to provide the title compound. Ms: m/z = 247.1). 106557.doc 103- 1312682 Preparation 5 1 4-Ethoxy-2-fluoro-N-methoxy-N-indolyl-benzamide according to the preparation of N-methoxyoxy_N-methyl_4_( Procedure for quinoline 2 - yloxy) phenylcarboxamide but substituting 4-ethoxy-2-fluoro-benzoic acid to provide the title compound. MS: (M+H m/z = 290.2). Preparation 52 1-(4-Benzyloxy-2-fluoro-styl)_2_α-pyridyl-4-yl-ethanone according to the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2- The procedure for the benzyloxy)-phenyl]-ethyl bromide but substituting 4-benzyloxy-2.fluoro-indole-methoxy-indole-methyl-p-carbamoylamine to afford the title compound. MS: (M+H m/z = 322.1). Preparation 53 4-[3-(4-Enooxy-2_fluoro-phenyl)small methyl-1H_„p. 44_yl]pyridinium according to the preparation 4·[3-(4-benzyloxy) Procedure for phenyl)_1-decyl-1H-indazol-4-yl]-pyridine but with 丨_(4_benzyloxy_2_fluoro-phenyl)_2-pyridine-4-yl-ethanone </ RTI> <RTIgt; The phenol is prepared according to the procedure for the preparation of 4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol but 4-[3_(4-benzyloxy-2- Fluoro-phenyl)-1-methyl-1H-.bizozol-4-yl]-bite substituting ' to provide the title compound. MS ·· (M+H m/z=270.1). Example 65 2 [3 -Fluoro-4-(1-methyl_4_σ-pyridyl_4_yl-1H-pyrazole-3-yl)-phenoxymethyl]-quinoline in 3-fluoro-4-(1-methyl _4_pyridine_4_yl-1H_pyrazole-3_yl)·phenol (45〇106557.doc -104· 1312682 mg) of didecylguanamine (l〇ml) solution was added with carbonic acid ( 2 g) and 2-chloromethyl-ethyl (481 mg) and the reaction mixture was heated at 60 ° C for 18 hours. The reaction mixture was poured into 1 NaOH, extracted with methylene chloride and dried over magnesium sulfate. Filter and Purification in Biotage MPLC, elution with methanol 2% / 0.5% ammonium hydroxide / 70% ethyl acetate / hexanes to afford the title compound. The white precipitate was added and the title compound was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (d, J=6.2 Hz, 2H), 8.26 (s5 1H), 8.00 (m, 2H), 7.78 (t, J=7.1 Hz, 1H), 7.70 (d, J=8.3 Hz, 1 H), 7.61 (t, J = 6.6 Hz, 1 H), 7.38 (t, J = 8.3, Hz, 1 H), 7.10 (d, J = 6.2

Hz, 2H), 7.00 (m5 2H), 5.40 (s, 2H), 3.88 (s, 3 H), 2.38 (s, 4H); MS . (M+H m/z=411.1) 0 Preparation 55 4 -[3-(4-Pheptyloxy_2.£-phenylpyrazole-4.yl)-picidine• According to the preparation of 2-[4-(4-. than 唆-4-yl-1H-» than saliva Procedure for the preparation of -3 -yl)-phenoxymethyl]-quinoline but substituting 1 (4. benzyloxy-2-fluoro-phenylpyridinyl-4-yl-ethyl bromide) to provide the title compound. : (M+H m/z = 346.3) Preparation 5 6 4-[3_(4-Benzyloxy-2-fluoro-phenyl)4-(2,2,2-trifluoro-ethylpyrazole _4· base]-° ratio bite according to the preparation of 2-{4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)_1H-pyrazole-3-yl]-phenoxy The procedure for the methyl}-quinoline was replaced by 4-[3-(4-benzyloxy-2-fluoro-phenyl)-1 Η-. instead of </RTI> <RTIgt; MS: 106557.doc -105 - 1312682 (M+H m/z = 428.4). Preparation 57 3- -4-[4- 〇 咬 -4- -4-yl-l-(2, 2, 2- Fluoro-ethyl)_iH-n is more than indole-3-yl]-indole in 4-[3-(4-benzyloxy-2-fluoro-phenyl)-1-(2,2,2-trifluoro- Trifluoroacetic acid (5.25 ml) and anisole (1.15 ml) were added to ethyl oxazol-4-yl]-pyridine (900 mg) and the reaction mixture was heated under reflux for 18 h. The reaction mixture was quenched with EtOAc (EtOAc EtOAc (EtOAc m. 552 mg). MS: (M+H m/z = 338.2). Example 66 2-{3- -4-[4-indole-But-4-yl-1-(2,2,2-trifluoro -ethyl)-11^-0 than 〇-3-yl]-phenoxymethyl}-quinoline according to the preparation of 2-[3-fluoro-4-(1-methyl-4-pyridine-4- Procedure for benzyl-1H-pyrazole-3-yl)-phenoxymethyl]-quinoline but with 3-fluoro-4-[4-.pyridin-4-yl-l-(2,2,2 -H.sub.2 NMR (400 MHz, CDC13) δ 8.46 (m, 2 Η), </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 7.80 (s, 1Η), 7.31 (t, J=8.3 Hz, 1H), 7.24 (m, 5 H), 6.72 (dd, J=8.3, 2.5 Hz, 1 H), 6.50 (dd, J=11.6, 2.1 Hz, 1 H), 4.81 (q, J = 8.4 Hz, 2H); MS: (M+H m/z = 479.2). Example 67 2-{3-Fluoro-4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1Η-pyrazole-3.yl]-phenoxymethyl Preparation of 2-[3-fluoro-4-(1-methyl-4-pyridin-4-yl-1Η-pyrazol-3-yl)-106557.doc • 106- 1312682 phenoxy The base of a group of μ 嗜 琳 之 之 % % % % % % % % % % % % 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心The morpholine and the propylamine are used as a solvent to provide the title compound. 1H NMR (400 MHz, CDC13) δ 9.09 (s, 1 Η), 8.46 (m, 2H), 8.15 (m, 1H), 8.09 (m, 1 Η), 7.8I (m, 3H), 7.43 (t , J=8.7Hz, 1H), 7.12 (d, J 6.2Hz, 2H), 6.93 (dd, J=7.9, 2.0 Hz, 1 H), 6.81 (dd, J 11.6, 2.5 Hz, 1 H), 5.43 (s, 2H), 4.80 (q, J = 8.3 Hz, 2H); MS: (M+H m/z = 48 〇.l). Example 68 4-Chloro-2-[4-(l-methylpyridine-4-yl-1H-pyrazole-3-yl)-phenoxyindolyl]-quinoline according to the preparation 2-{4-[4 · Pyridyl-1·(2,2,2-trifluoro-ethyl)_1Η_&lt;oxazol-3-yl]-phenoxymethylbuquinoxaline procedure but with 4_(1 methyl- 4pyridine- Substituting 4-yl-1H-pyrazol-3-yl)-phenol and (4-a-quinolin-2-yl)-methanol to afford the title compound. 1H NMR (400 MHz, CDC1J δ 8.43 (d, J=4.6

Hz, 2 H), 8.18 (d, J=8.7 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.73 (m, 2H), 7.60 (t, J=7.1 Hz, 1 H), 7.52 (s, 1 H), 7.37 (d, J=9.1, Hz, 2 H), 7.12 (d, J=6.2 Hz, 2H), 6.98 (d, J=8.7 Hz, 2 H), 5.30 (s , 2H), 3.90 (s, 3 H); MS: (M+H m/z = 427.1). Example 69 4-Methoxy-2-[4-(l-methyl-4-pyridin-4-yl-1Η-η-pyrazol-3-yl)-p-oxymethyl]-quinoline in 4- Gas-2-[4-(1-methyl-4-.pyridin-4-yl-1^1-°boxazol-3-yl)-phenoxymethyl]-quinoline (125 mg) In the sterol (4 mL) solution, phenanthrene 106557.doc • 107· 1312682 (phenanthroline) (78 mg), carbonated (143 mg) and copper iodide (5 mg) were added. The reaction mixture was heated in a microwave reactor at 165 ° C for 20 minutes at 50 watts. The reaction mixture was filtered through celite and concentrated. Purification by mplc biotage chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) NMR (400 MHz, CDC13) δ 8.45 (d, J = 5.4 Hz, 2 H), 8.18 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.68 (m, 1H) ), 7.55 (s, 1H), 7.49 (t, J=7.1 Hz, 1 H), 7.37 (d, J=9.1, Hz, 2 H), 7.15 (d, J=6.2 Hz, 2H), 7.01 ( m, 3H), 5.32 (s, 2H), 4.02 (s, 3 H), 3.95 (s, 3H); MS: (M+H m/z = 423_3). Example 70 Dimethyl-{2-[4-(l-methyl-4-pyridin-4-yl-1H-&quot;pyrazol-3-yl)-phenoxymethyl]-quinolin-4- a 5-amine-2-[4-(1-methyl-4-«pyridin-4-yl-1H-indazol-3-yl)-phenoxymethyl]-quinoline ( To a solution of 135 mg) in tetrahydrofuran (4 mL), add decylamine (2N of the solution of '20.3 mL), fluorinated (5 mg), diisopropylethylamine (62 mg) and tetrabutyl Ammonium (12 mg). The reaction mixture was heated in a microwave reactor at 180 ° C for 40 minutes at 100 watts. The reaction mixture was passed through a pad of Celite and concentrated. Purified by MPLC biotage chromatography to 5% decyl alcohol / 1 ° /. Ammonium hydroxide / hydrazinyl chloride was dissolved to give the title compound (36 mg) 〇!H NMR (400 MHz, CDC13) δ 8.45 (d, J = 6.2 Hz, 2 H), 8.04 (d, J = 8.3 Hz , 1H), 7.99 (d, J=8.3 Hz, 1H), 7.62 (m, 1H), 7.56 (s, 1H), 7.42 (m, 1 H), 7.38 (d, J=9.1 Hz, 2 H) , 7.15 (d, J=6.2 Hz, 2H), 7.01 (m, 3H), 5.29 (s, 2H), 3.95 (s, 3 H), 3.03 106557.doc -108- 1312682 (s, 6H); MS :(M+hm/z=436 3) 0 Preparation 58 N-Methoxy-indole-methyl_4_triisopropyldecyloxymethyl-benzamide The preparation of 4-benzyloxy The procedure for -N-methoxy-N-methyl-benzamide was replaced with 4-triisopropyl oxalyloxymethyl-benzoic acid to afford the title compound. MS: (M+Hm/z = 352 1}. Preparation 59 2-n ratio -4-amino·ι_(4·triisopropyldecyloxycarbonyl-phenyl)-ethanone according to Preparation 1 -(4-Benzyloxy-phenyl)_2-pyridin-4-yl-ethanone procedure but with N-methoxy_N_methyltriisopropyldecyloxymethyl-benzamide Replace ' to provide the title compound. MS: (M+H m/z = 3 84.1). Preparation 60 4-indole-methyl 3-(4-triisopropyldecyloxymethyl-phenyl) _1H_pyrazol-4-yl]-. The ratio of 4-[3-(4-hydroxy-phenyl)-1-methyl-ΐΗ-β to ol-4-yl]·° The procedure for the pyridine was replaced by 2-pyridin-4-yl-1-(4-triisopropyldecyloxymethyl-phenyl)-ethanone to give the title compound. MS: (M+H m/ z= 422.2) 〇Preparation 61 [4-(1-methyl-4-0 is more than -4-yl-1H-0 than 0--3-yl)-phenyl]-methanol in 4-[1- Add TBAF (1.0) to a solution of hydrazino-3-(4-triisopropyl oxalyloxymethyl-phenyl)_ih_. oxazol-4-yl]-pyridine (1.75 g) in THF (16.2 mL) M THF, 5.2 mL) and the reaction mixture was stirred at ambient temperature in an inert atmosphere for 1 hour. The reaction mixture was poured into saturated sodium bicarbonate. Extracted three times with 106557.doc -109· 1312682 chloroform, dried over magnesium sulfate, filtered and concentrated. Purified by MPLC biotage chromatography '2° / methanol / 0.5% saturated ammonium hydroxide / 50% ethyl acetate / The hexane was dissolved to give the title compound (920 mg, 84%). MS: (M+H m/z=266.1). Example 71 2-[4-(1-methyl-4-0 ratio bite-4 -Base-1H-D ratio. Sodium-3-yl)-oxyl group]_啥吓_disuccinic acid

Preparation of 2-{4_[4-pyridine-4-yl-1-(2,2,2-trifluoro-ethyl)-111-pyrazol-3-yl]-phenoxyindolyl}-quinoxaline Procedure, but substituted with [4_(ι_methyl_4_pyridin-4-yl-1Η-» than indol-3-yl)-phenyl]-methanol and hydrazine-2-ol to provide the title compound . 1H NMR (400 MHz, DMS0) δ 8.42 (d, J = 5.0 Hz, 2 H), 8.25 (d, J = 8.7 Hz, 1H), 8.14 (s, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.66 (t, J=7.1 Hz, 1 H), 7.51 (d, J=7.5 Hz, 2 H), 7.40 (m, 3 H), 7.19 (d, J=4.6 Hz, 2H), 7.07 (d, J=8.7 Hz, 1H), 5.49 (s, 2H), 2.38 (s, 8 H); MS : (M+H m/z=393.1) . Preparation 62 N_((4-(Hydroxy)phenyl) (p-phenylphenyl)methyl)caraamine in 4-methylphenyl hydrazide complex (3.1 g, 19 9 mm 〇 1) , 4_(oxy)oxybenzole (4.2 g, 19.9 mmol) of f-amine (45 mL) mixture was heated at (10). The mixture was diluted with methanol and continuously stirred at room temperature for 1 hour. The solid was filtered and dried <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> 3, 81 g (49%) of white solid. The product was used in the next step without purification. Preparations 63 106 557.doc -110 - 1312682 1-( (4-(Benzyloxy)phenyl)isocyanatomethylsulfonyl)-4-methylbenzene in N-((4-(benzyloxy)phenyl)(p-toluenesulfonyl)methyl)methyl醯 ο 〗 〖 g, 8.1 mmol) 43 mL of DME (dimethoxyethane) solution was added to P0C13 (2.27 mL) in ye, followed by dropwise addition of triethylamine (5 6 mL). The resulting solution was stirred at ΟΥ for 3 hours and finally poured into cold water. The precipitate was collected and dried to give 3.3 g of a pale yellow solid. MS m/z: 378 [M+l]+. Preparation 64 4-(4-(4-(Benzyloxy)phenyl), 嗤_5_yl) bite at 1-((4-(benzyloxy)phenyl)isocyanatomethylsulfonate Methylbenzene (43 g, 11.4 mmol), different from acid (1.34 g, 12.5 mmol) and K2C03 (3.15 g, 22.8 mmol) in decyl alcohol (96 mL) and DME (30 mL) The mixture was heated under reflux for 5 hours. After removal of the solvent, the residue was purified by EtOAc (EtOAc:EtOAc:EtOAc) NMR (400 MHz, CDC13) δ: 5.12ν (s, 2Η), 7.03 (d, 2Η), 7.46 (m, 6H), 7.56 (d, 2H), 7.61 (d, 2H), 8.02 (s, 1H ), 8.58 (d, 2H). MS m/z : 329 [M+l]+. Preparation 65 4-(5-(° ratio -4- base) is expected to be 4-(4-(4-(benzyloxy)phenyl)oxazol-5-yl). A solution of 20% Pd(OH)2/C (30 mg) and formic acid (115 mg, 1.83 mmol) in methanol (8 mL) was added to a solution of g, 0.91 mmol). The solution was heated at 60 °C. The catalyst was removed by filtration and the filtrate was concentrated to give 208 mg (yield: 96%) of the title compound. 1H NMR (400 MHz, CDC13) δ: 6.92 (m, 106557.doc -Ill - 1312682 2H), 7.46 ( m, 2H), 7.57 (d, 2H), 8.02 (s, 1H), 8.58 (m, 2H). MS m/z: 239 [M+l]+. Example 72 2-((4-(5- (Bite _4_ base) No. 11. Sodium-4-yl)phenoxy)methyl) 喧 in the compound 4-(5-(pyridin-4-yl)oxazol-4-yl)phenol (90 mg Add CsF (115 mg, 0.76 mmol) to 1 mL of dry DMF solution in 0.38 mmol). After stirring for 0.5 h, add 2-(chloromethyl) sulfonate (67 mg, 0.38 mmol) and react at 80 The mixture was heated to EtOAc (EtOAc) (EtOAc). δ : 5.47 (s, 2H), 7.11 (m, 2H), 7.56 (m, 5H), 7.70 (d, 1H), 7.78 (t, 1H), 7.86 (d, 1H), 8.01 (s, 1H), 8.12 (d, 1H), 8.26 (d, 1H ), 8.57 (d, (2H). MS m/z: 380 [M+l]+. Preparation 66 1-(4-(benzyloxy)phenyl)_2-bromo-2 (e. -Acetyl ketone in 1-(4-(benzyloxy)phenylpyridin-4-yl)ethanone (1.39 g, 4.58 mmol) in acetic acid solution (0.72 g, 4.58 mmol) of acetic acid (3) </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1H), 7.15 (d, 2H), 7.42 (m, 3H), 7.87 (m, 1H), 8.06 (d, 2H), 8.77 (m, 1H). MS m/z : 382 [M+l]+ . Preparation 67 4-(4-(4-(Hydroxy)phenyl)_2-methylcarbazole-5-yl)pyridinium 106557.doc -112- 1312682 in sodium acetate (323 mg, 2.38 mmol) Add 1-(4-(benzyloxy)phenyl)·2_ &gt; odor-2-(n to 唆-4-yl) to a mixture of acetic acid (304 mg, 3.95 mmol) in acetic acid (10 mL) Acetamide (302 mg, 0.79 mmol). The resulting mixture was refluxed for 48 hours. After the solvent was removed in vacuo, the residue was dissolved in ethyl acetate. The organic phase was dried and concentrated in vacuo to give a crude oil, which was purified by chromatography (1:3 EtOAc / hexanes) to afford in mg (41%). NMR (400 MHz, CDC13) δ: 2.58 (s, 3Η), 5.15 (s, 2H), 7.01 (d, 2H), 7.39 (m, 7H), 7.56 (d, 2H), 8.57 (d, 2H) MS m/z : 343 [M+l]+. Preparation 68 4-(2-Methyl-5-(indenyl)-4-indolyl-4-yl) 4-(4-(4-(benzyloxy)phenyl)-2- Methylcarbazole-5-yl)acridine is 5 Torr in the presence of ammonium formate and Pd(OH)2 in methanol. (: Hydrogenation for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated. The residue obtained was dissolved in methylene hexanes and dried over NajO4. The solvent was evaporated to give 69 mg (86%) of Solid MS m/z: 253. Example 73 2-((4-(2-methyl-5-(pyridin-4-yl)oxazol-4-yl)phenoxy)methyl)quinoline in 4 -(2-Methyl-5-(Bite-4-yl)&gt;» 嗤-4-yl) Add Cs2C〇3 to 2·5 mL of dry DMF solution (21 mg, 0.083 mmol) 54 mg, 〇17 mmol). After stirring for 5 hours, add 2-(aeromethyl)quinolin (17.8 mg, o.ioo mmol) and mix the mixture at 85. Mix for 12 hours in vacuo. After the DMF was removed, the residue was purified with EtOAc EtOAc (EtOAc: EtOAc (EtOAc) : 2.54 (s, 3H), 5.41 (s, 2H), 7.06 (m, 2H), 7.41 (m, 2H), 7.53 (m, 3H), 7.68 (d, 1H), 7.80 (t, 1H), 7.83 (d, 1H), 8.05 (d, 1H), 8.20 (d, 1H), 8.53 (m, 2H). MS m/z: 394 [M+l] +. Preparation 69 4-(4-( (噎琳-2-yl)methoxy)phenyl -3_(pyridine-4-yl)butyr-3-ene-2-ketone• In 4-(((琳-2-yl)methoxy)benzaldehyde (2.5 g, 9.5 mmol), 1-(pyridinium- 4-Methylpropane 3 g, 9.5 mmol) and 0 bottom bit (162 mg, 1.9 mmol) in toluene (5 mL) mixture were heated under reflux for 18 hours, concentrated and the residue was chromatographed. Dissolve in a hexane gradient of ethyl acetate to give the title compound (2 4 g) as a yellow solid, which was again chromatographed on silica gel with 1% and 2% methanol in methane. The process is carried out, and the system contains 〇·5. /❶ concentrated ammonium hydroxide to obtain a mixture of the title material and the pyridyl starting material in a mixture of 3:!. Yield 2 〇 g, 55%. Φ The title material was found to be a 10··1 mixture of diisomers by NMR. 1H NMr (CDC13, 400 mHz, part) 2.35 (s, 3H, major isomer), 2 23 (s, 3H' minor isomer). HpLC_MS 6 〇9 Theory, Oil 38ι (Dimensional Small Example 74 2-((4-(3-Methyl-4)-Bit 4·yl)_m"Bis.5-yl)phenoxy)methyl)嗜来将(心木_2_基)曱oxy)phenyl)·3十比基基)丁_3_埽_2-ketone (1.〇0§'2.6〇_〇1) and _ A mixture of acetic acid (14 mL) of terpene sulfonate-based cultivating (484 called 26 〇1) was heated under reflux for 1 hour. Add an additional 106557.doc -114· 1312682

The p-toluenesulfonyl hydrazide (242 mg, 0.5 mmol) was added and the mixture was heated under reflux for 2 hr. The mixture was concentrated, the residue was taken up in di-methane, and the obtained mixture was washed with water (2×25 mL), dried and concentrated. The residue was chromatographed and dissolved on a silica gel in a solution of 1 〇 / 〇, 2 〇 / 〇 and 3 〇 / sterol in methylene chloride containing 〇. 5% concentrated ammonium hydroxide to obtain a The solid was wet-ground with diethyl ether and dried. Yield 293 mg, 29%. Lpi NM]R (CDC13, 400 mHz) δ 8.51 (m, 2H), 8.18 (d, 1H, J = 8.7 Hz), • 8'06 (d, 1H, J - 7_9 Hz), 7.81 (d, 1H , J = 8_3 Hz), 7.72 (m, 1H), 7.64 (d, 1H, J = 8.3 Hz), 7.54 (m, 1H), 7.24 (m, 2H), 7.13 (m, 2H), 6.96 (m&gt 2H), 5.36 (s, 2H), 2.33 (s, 3H) 〇HPLC-MS (System 1) 4.65 min, m/e 393 (MH+). Example 75 2-((4-(1,3-Bisinyl_4_(n-pyridyl_4_*)_1H_0-biazole-5-phenyl)phenoxy)methyl)indole in 2-((4·( Anhydrous dimethyl 3-methyl-4-(acridine-4-yl)-1Η-pyrazol-5-yl)phenoxy)methylsulfanylquinoline (15〇mg, 〇·38 mmo1) A solution of methotrexate (2 mL) was applied to the hydrazine.处理 Treated with a sodium hydride dispersion (30 mg, 0 76 〇1 in 6% blue in oil), followed by iodomethane (54 mg, 0.38 mmol) for 20 minutes and allowed to warm the mixture until RT and overnight. Water was added and the mixture was extracted with dichlorohydrazine (3 x 20 mL). The organic layer was dried and concentrated, and the residue was subjected to chromatography, and eluted on a mixture of triethylacetate and ethyl acetate-hexanes to obtain a mixture containing two isomeric substances. Thus, a less polar isomer can be obtained ([8(7) is chemically experimentally determined by NMR with a methylation reaction zone). 4 NMR (CDCl3, 106557.doc -115- 1312682 400 mHz) δ 8.41 (m, 2H), 8.21 (d, 1H, J = 8.7 Hz), 8.07 (d, 1H, J = 8.3 Hz), 7.84 (d , 1H, J = 9.5 Hz), 7.74 (ddd, 1H), 7.67 (d, 1H, J = 8.3 Hz), 7.55 (ddd, 1H), 7.12 (m, 2H), 7.05 (m, 2H), 7.0 (m, 2H), 5.40 (s, 2H), 3.71 (s, 3H), 2 37 (s, 3H). HPLC-MS 4.81 min, m/e 407 (MH+). Example 76 2-((4-(1,5-Dimethyl_4_(0-pyridyl-4-yl)) Η..Byrazole-3-yl)phenoxy)methyl)indole by 2-(( Comparison of alkylation of sodium hydride/iodomethane with 4-(3-methyl-4-decapyridin-4-yl)·1Η-«bisazol-5-yl)phenoxy)methyl)quinoline With a polar dissolving fraction, 26 mg of impure title material can be provided which can be recrystallized from 10: i ethyl acetate-hexane to give a pure substance having a homogeneity, the chemistry of the thiolation reaction zone being experimentally determined by NMR. 4 NMR (CDC13, 400 mHz) δ 8.51 (m, 2H), 8.17 (d, 1H, J = 8.7 Hz), 8.05 (d, 1H, J = 8.3 Hz), 7.85 (d, 1H, J = 8.3 Hz) ), 7.72 (ddd, 1H), 7.65 (d, 1H, J = 8.7 Hz), 7.53 (t, 1H, J = 7.5 Hz), 7.27 (m, 2H), 7.12-7.11 (m, 2H), 6.93 (m, 2H), 5.36 (s, 2H), 3.87 (s, 3H), 2.30 (s, 3H). HPLC-MS 4.78 min, m/e 407 (MH+). Preparation 6 9 a 1-(quinolin-2-yl)ethanol Methylmagnesium bromide (17·6 mL of 1.4 Torr in toluene, 24.7 mm 〇i) was added to 啥琳-2- at less than 10 C The mixture was stirred at room temperature for 1 hour, and poured into a saturated aqueous solution of ammonium chloride (100 mL), and then obtained. The mixture was extracted with acetic acid 106557.doc • 116-1312682 ethyl acetate (3 x 150 mL). The extract was dried, concentrated, and the residue was chromatographed eluting with EtOAc EtOAc EtOAc EtOAc The yield was 2.46 g, 75%. Η NMR (CDC13, 400 mHz) δ 8.15 (d, 1Η, J= 8.7 Hz), 8.07 (d, 1H, J = 8.7 Hz), 7.81 (dd, 1H, J = 1, 8 Hz), 7.71 (ddd , 1H, J =

Hz), 7.51 (ddd, 1H, J = 1, 7, 8.3 Hz), 7.33 (d, 1H, J = 8-3 Hz), 5.07-4.99 (m, 2H), 1.56 (d, 3H, J= 6.2 Hz) 〇Example 77 2 (1 (4 (1-methyl_4_(〇比 bit_4·基)_出_0 ratio 0 sit _3_基)phenoxy) ethyl)喧琳4- (1-Methyl-4·(pyridine·4-yl)_1H-pyrazol-3-yl)phenol (75 mg, 0.30 mm〇l) and 1-(quinolin-2-yl)ethanol (78 mg, 0.45) Methyl)-p-dioxane (2 mL) mixture was sequentially subjected to triphenylphosphine (126 mg, 0.48 mm 〇1) and di-tert-butyl diazodicarboxylate (110 mg) at room temperature. , 0. 48 mmol) was treated and the mixture was taken to 6 Torr. Heat under the arm for 4 hours. A 2N aqueous NaOH solution was added and the mixture was extracted with dichloromethane. The organic layer was dried <RTI ID=0.0></RTI> to EtOAc. Yield 36 mg, 29%. 4 NMR (CDC13, 400 mHz) δ 8.40 (m, 2H), 8.10 (d, 1H, J = 8.7 Hz), 8.06 (d, 1H, J = 7.5 Hz), 7.77 (d, 1H, J = 8.3 Hz) ), 7.71 (ddd, 1H), 7.55 (d, 1H, J = 8.3 Hz), 7.53-7.49 (m, 2H), 7.25 (m, 2H), 7.10 (m, 2H), 6.88 (m, 2H) , 5.59 (q, 1H, J = 6.6 Hz), 3.91 (s, 3H), 1.75 (d, 3H, J = 6.6 Hz). HPLC-MS (System 1) 4.73 min, m/e 407 (MH+). 106557.doc -117- 1312682 Preparation 70 2-((4-(2-(»-pyridine-4-yl)ethynyl)phenoxy)methyl)quinoline 4-(2-(° ratio bite a mixture of hydrogen chloride (385 mg, 1.8 mmol) and cesium carbonate (2.2 g, 687 mmol) in dimethylformamide (8 mL) at 65. Stir for 3 hours. Water was added (20 mL) and the mixture was extracted with dichloromethane (3×l 5 mL). The organic layer was dried <RTI ID=0.0></RTI> to <RTI ID=0.0> iH NMR (CDCl3, 4〇〇mHz) § 8 % 2H), 8.20 (d, 1H, J = 8.7 Hz), 8.08 (d, 1H, J = 8.3 Hz), 7.82 (d, 1H, J = 7.9 Hz) ), 7.74 (ddd, 1H, J = 8.4, 7, 1Hz), 7.63 (d, 1H, J = 8.7 Hz), 7.55 (ddd, 1H, J = 8, 7, 1 Hz), 7.47 (m, 2H) ), 7.35 (m, 2H), 7.01 (m, 2H), 5.41 (s, 2H). MS (AP+) m/e 337 (MH+). Preparation 71 4-(2-(pyridin-4-yl)ethynyl)phenol Addition of three deserts (1 M dioxin, 97 mL, 9·7 〇1) at 0 °C a solution of 4-(2-(4-methoxyphenyl)ethynyl)pyridine (81 mg, 388 mm 〇1) in dichloromethane (10 mL). Aqueous sodium hydroxide (20 mL) was added and the pH was adjusted between 7 and 8 after 4 min. The resulting mixture was extracted with 4: chloroformamide: 2-propanol (3 x 3 GmL). The organic layer was dried, concentrated and evaporated, and the residue was chromatographed on (4) from 25% to 80%. The mixture was dissolved in a gradient of hexanes to dryness to give a brown solid. Yield "ο 106557.doc -118· 1312682 mg, 60°/〇.ifi NMR (CDC13, containing CD3OD, 400 mHz) δ 8.50 (br, 2H), 7.38 (br, 2H), 7.37 (d, 2H, J = 8.7 Hz), 6.77 (d, 2H, J = 8.7 Hz), 3.11 (br, 2H, OH + H20). MS (AP+) m/e 196 (MH+). Preparation 72 4-(2-(4) -Methoxyphenyl)ethynyl)acridine 4-methoxyphenylacetylene (2.86 g, 21.7 mmol), 4-breaking 0 bite (4.44 g, 21.7 mmol), cuprous iodide (206 mg , 1.08 mmol), a mixture of bis(triphenylphosphine)palladium (11) (758 mg, 1.08 mmol) in tetrahydrofuran (40 mL) and triethylamine (20 mL). The mixture was filtered, concentrated, and the residue was chromatographed eluted EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc ) δ 9·2 (extremely wide, 2H), 7.57 (br, 2H), 7.48 (d, 2H, J = 8.7 Hz), 6.88 (d, 2H, J = 8·7 Hz), 3.82 (s, 3H) MS (AP+) m/e 210 (MH+) 〇 Example 78 2-((4-(5-(pyridin-4-yl)-1,2,3-triazol-4-yl)phenyloxy) Methyl)quinoline trimethyldecylmethyl azide (73 0 mg, 6.4 mmol) and 2-((4-(2-(pyridin-4-yl)ethynyl)phenoxy)indolyl)quinoline (36 〇mg) - placed in a sealed tube with a screw cap And heated in a 150 ° C oil bath for 72 hours behind a safety shield. The mixture was concentrated and the yellow residue was triturated with _i (2×10 mL) to leave a yellow solid (346 mg). Chromatography on silica gel, eluting with a gradient of 0.5% to 2 hydrazine/methanol in dichloromethane to give a yellow solid (210 mg, 52%). 4 NMR (CDC13, containing 106557.doc -119. 1312682 a drop of CD3OD, 400 mHz) δ 8.54 (d, 2H, J = 6.2 Hz), 8.23 (d, 1H, J = 8.7 Hz), 8.07 (d, 1H, J = 8.7 Hz), 7.84 (d, 1H, J = 7.9

Hz), 7.74 (ddd, 1H, J = 8.4, 7, 1Hz), 7.69 (d, 1H, J = 8.7 Hz), 7.63 (d, 2H, J = 6.2 Hz), 7.56 (ddd, 1H), 7.41 (m, 2H), 7.09 (m, 2H), 5.41 (s, 2H). MS (AP+) m/e 380 (MH+). Preparation 73 4-(2-Methyl-5-(pyridin-4-yl)-2H-l,2,3-triazol-4-yl)phenol 4-(5-(4-methoxybenzene) a solution of 2,3,3,2,2,3,3-triazolyl) (2,3 mL, 203 mg, 0.76 mmol) in dichloromethane (5 mL) 1 Μ 二 气 methane solution) and the mixture was stirred at room temperature for 18 hours. Methanol (3 mL) was added and the mixture was concentrated and extracted with methylene chloride and aqueous sodium hydrogen carbonate. The organic extract is dried and concentrated to give a yellow solid which can be chromatographed on silica gel ( gradient of 5%-3% methanol in dioxin) to give two substances: a more polar material (88 mg) It was identified as 4-(2-methyl-5-(pyridin-4-yl)-2Η-1,2,3-triazol-4-yl)phenol. 1H NMR (CDC13, 400 mHz, part) δ 8.57 (br, 2 Η), 7.59 (d, 2 Η, J = 5.2 Hz), 7.32 (m, 2H), 6.90 (m, 2H), 4.26 (s, 3H) ). HPLC-MS (System 1) 3 _96 min, m/e 253 (MH+). The less polar material (80 mg) was identified as the corresponding boric acid, which was found to be converted to a less polar material by treatment with aqueous NaOH. Preparation 74 4-(5-(4-Methoxyphenyl)-2-methyl-2H-1,2,3-triazol-4-yl)pyridine, 4-(5-(4-methoxy) Phenyl)·1·methyl-1H_triazole_4_yl)pyridine and 4-(5-(4-methoxyphenyl)-3-methyl-3H-1,2,3-triazole 4-yl)pyridine 106557.doc • 120· 1312682 Sodium hydride (240 mg of 60% oil dispersion, 6.0 mmol) was added to hydrazine. Add hydrazine to 4-(5-(4-methoxyphenyl)-1,2,3-triazol-4-yl)pyridine (755 mg, 3.0 mmol) of dimethyl decylamine (1 mL) In the solution, the mixture was stirred for 30 minutes. Methyl iodide (425 mg) was added and the mixture was stirred for 2.5 hours, quenched with water (20 mL) and extracted with dioxane (3×20 mL). The organic layer was dried using magnesium sulfate and concentrated. The residue was chromatographed on silica gel and eluted with a gradient of 50% to 100% ethyl acetate-hexane to afford three tolu. Each showed the mass m/e 267 (MH+) by HPLC-MS. Each structure was determined by single crystal X-ray in crystals grown from ethyl acetate or acetonitrile. Minimum polar material (454 mg of yellow solid), 4-(5-(4-methoxyphenyl)-2-methyl·2Η-1,2,3-triazol-4-yl)pyridine, 4 NMR (CDC13, 400 mHz) δ 8.59 (br, 2Η), 7.52 (br, 2H), 7.41 (m, 2H), 6.93 (m, 2H), 4.26 (s, 3H), 3.84 (s, 3H). Medium polar material (235 mg yellow solid), 4-(5-(4-methoxyphenyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine, hNMRCCDCUMOO mHz) 8.49 (d, 2H, J = 6.22), 7.52 (m, 2H), 7.24 (m, 2H), 7.06 (m, 2H), 3.91 (s, 3H), 3.89 (s, 3H). The highest polar substance (5 〇 mg yellow solid), 4-(5-(4-methoxyphenyl)·3-methyl-3H-1,2,3-triazol-4-yl) pyridine, 4 NMR (CDC13, 400 mHz) 8.59 (br, 2H), 7.52 (br, 2H), 7.41 (m, 2H), 6.93 (m, 2H), 4.26 (s, 3H), 3.84 (s, 3H) 〇 Preparation 75 4-(5-(4-Methoxyphenyl)-1,2,3-trimethyl-4-yl)D ratio 4-(2-(4-decyloxyphenyl)ethynyl β is pyridine (ι·48 g, 7.1 mm oi) and trimethyl sulphate methyl azide (2.5 g, 21.3 mmol) - placed in a sealed tube placed 106557.doc -121 - 1312682 at 150. (3) Heating in an oil bath for 48 hours. The mixture was chromatographed eluted EtOAc EtOAc EtOAc (EtOAc) 2H, J = 5.8 Hz), 7.60 (d, 2H, J = 5.8 Hz), 7.36 (d, 2H, J = 8.7 Hz), 6.92 (d, 2H, J = B.7 Hz), 3.81 (s, 3H), 2.80 (br, 1H). MS (AP+) m/e 253 (MH+). Example 79 2-((4-(2-methyl- 5-(〇))) 1,2,3-trimethyl-4-yl)phenoxy)indenyl)quinoline

4-(2-Methyl-5-(0-pyridin-4-yl)-211-1,2,3-tris-yt-4-yl) (80 mg, 0.32 mmol), 2-( a mixture of gas methyl)quinoline hydrogenated hydrogen (71 mg, 0.33 mg) and dithiocarbazide (414 mg, 1.27 mmol) in dimethylformamide at 65 ° C for 20 hours and filtered, the filtrate was concentrated and Chromatographic separation on silica gel was carried out with acetic acid to provide a starting material. This was dissolved in ethyl acetate, washed with EtOAc aq. 4 NMR (CDC13, 400 mHz) δ 8.56 (d, 2H, J = 6.2 Hz), 8.24 (d, 1H, J = 8.3 Hz), 8.12 (d, 1H, J = 8.3 Hz), 7.85 (d, 1H , J = 8.3 Hz), 7.75 (ddd, 1H, J = 8.5, 7, 1.6 Hz), 7.70 (d, 1H, J = 8.7 Hz), 7.65 (d, 2H, J = 6.2 Hz), 7.57 (m , 1H), 7.41 (m, 2H), 7.08 (m, 2H), 5.45 (s, 2H), 4.27 (s, 3H). MS (AP+) m/e 394 (MH+). Preparation 76 4-(3-methyl-5-(〇比 bit_4_基)_31^_1,2,3_三0坐_4_基)4_(5_(4-methoxybenzene) Base)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine 106557.doc -122- 1312682 (170 mg, 0.64 mmol) in dioxane (5 mL) at room temperature Treatment with boron tribromide (1.27 mL of 1 M solution in di-methane) and stirring the mixture overnight. IN NaOH (10 mL) was added, and after stirring for 1 hour, the mixture was extracted with dichloromethane (2 mL). The aqueous layer was acidified to pH 7 using 2N EtOAc and extracted with ethyl acetate (2 EtOAc). The extract was dried over sodium sulphate and concentrated to give a yellow solid ( </RTI> <RTIgt; 4 NMR (CDCI3, 400 mHz) δ 8.39 (d, 2H, J = 5-6 Hz), 7.49 (d, 2H, J = 5-6 Hz), 7.09 (d, 2H, J = 8.7 Hz), 6.95 (d, 2H, J = 8.7 Hz) 3.87 (s, 3H). MS (AP-) 351 (MH). Example 80 2-((4-(3-Methyl-5-(pyridin-4-yl)-3H-l,2,3-triazol-4-yl)phenoxy)methyl)quinine 4 -(3·methyl-5-(0-indol-4-yl)-3Η-1,2,3-triterpenyl _4_yl) (88 mg, 0.3 5 mmol), 2-(chloroform) A mixture of quinoline hydrogen chloride (82 mg, 0.38 mmol) and carbonic acid planing (455 mg, 1.4 mmol) in dimethylformamide at 65.授 Mix for 20 hours, filter and concentrate. The residue was chromatographed on EtOAc EtOAc (EtOAc) 4 NMR (CDC13, 400 mHz) δ 8.48 (d, 2H, J = 6.2 Hz), 8.24 (d, 1H, J = 8.3 Hz), 8.09 (d, 1H, J = 8.3 Hz), 7.85 (d, 1H) , J = 7.9 Hz), 7.76 (ddd, 1H, J = 8.5, 7, 1Hz), 7.70 (d, 1H, J = 8.7 Hz), 7.57 (m, 1H), 7.54 (m, 2H), 7_24 ( m, 2H), 7.20 (m, 2H). 5.46 (s, 2H), 3.90 (s, 3H). MS (AP+) m/e 394 (MH+). Preparation 77 106557.doc -123 - 1312682 4-(1-(pyridin-4-yl)-1H-imidazol-2-yl)phenol According to the preparation of 4-(3-methyl-5-(pyridin-4-yl) )-3Η-1,2,3-三哇-4-yl) The method of 'except for 4. 1 squid: 2 -propanol used to replace ethyl acetate for extraction with 1.25 mmol of boron tribromide The treated product 4-(2-(4.methoxyphenyl)-1. sit-1 -yl)" bite (125 mg, 0.5 mmol) to give 90

Mg of solid waste. 4 NMR (CDC13, 400 mHz) δ 8.52 (d, 2H, J = 6 Hz), 7.14 (m, 2H), 7.11-7.08 (m, 4H), 6.79 (m, 2H), 2.94 (br, 1H) . &gt; Preparation 78 4-(2-(4-Methoxyphenyl)-iH-imidazol-1-yl)pyridine A five-gasified dish (572 mg, 2.75 mmol) was added to 4-methoxy A mixture of oxime-(»Bitter-4-yl)benzamide (626 mg, 2.75 mmol) in oxygenated dish (3 mL) and the mixture was heated in a 10 ° C oil bath for 4 hours. The mixture was concentrated to dryness. A solution of 2,2-dimethoxyethylamine (3.1 g) in methanol was added to the residue, and the mixture was stirred at RT. After more than one hour, &gt; was partially concentrated to remove most of the methanol, stirred at room temperature overnight and concentrated to dryness. Add isopropyl yeast (10 mL) and concentrate HCl (15 mL) and heat the mixture at 8 (TC for 24 hours. Add solid sodium cesium carbonate to adjust the pH to 7-8 and dioxane (3x50) The mixture was extracted with EtOAc (3 mL). 1H NMR (CDC13, 400 mHz) δ 8.55 (d, 2H, J = 6 Hz), 7.22 (d, 2H, J = 9 Hz), 7.17 (s, 1H), 7.12 (s, 1H), 7.05 (d , 2H, J=6 Hz), 6.75 (d, 2H, J=9 Hz), 3.72 (s, 3H). 106557.doc -124- 1312682 Preparation 79 4_Methoxy-N-decapyridin-4 Benzoamine Benzylamine 4-aminopyridine (1.94 g, 20.6 mmol) was added to p-methoxybenzyl fluorene (3.5 g, 20.6 mmol) and triethylamine (8·6). mL, 62 mm 〇 1) in dichloromethane (100 mL). The mixture was stirred at room temperature for 3 hr then extracted with 1N EtOAc, water and brine. Chromatographic separation (3% to 1% ethyl acetate-hexane gradient) was applied to silica gel to afford 3.8 g (81%) as a colorless solid. NMR (CDC13, 400 mHz) δ 8.49 (m, 2Η), 8.19 (br, 1H), 7.85 (m, 2H), 7.59 (m, 2H), 6.95 (m, 2H), 3.85 (s, 3H). MS (AP+) 229 (MH+). Example 8 1 2-((4-(1-(Pyridine-4-yl)-1Η-imidazol-2-yl)phenoxy)indolyl)quinoline according to the preparation of 2-((4-(3-) 5-(pyridin-4-yl)-3H-1,2,3-triazol-4-yl)phenoxy)methyl)quinoline, 4-(1-(pyridine-4-yl)- Procedure for 1 Η-imidazol-2-yl)phenol (90 mg) 2-(milk methyl) sulfonium chloride (81 mg) and carbonic acid (495 mg) afforded 120 mg of white solid (84%). 4 NMR (CDC13, 400 mHz) δ 8.59 (m, 2H), 8.16 (d, 1H, J = 8.3 Hz), 8.04 (d, 1H, J = 8.3 Hz), 7.79 (d, 1H, J = 7.9 Hz) ), 7.70 (ddd, 1H), 7.60 (d, 1H, J = 8.3 Hz), 7.52 (ddd, 1H), 7.28 (m, 2H), 7.22 (d, 1H, J =1 Hz), 7.15 (d , 1H, J = 1 Hz), 7.11 (m, 2H), 6.94 (m, 2H), 5.3 4 (s, 2H). HPLC-MS (System l) 4.53 min, m/e 379 (MH+). Preparation 8 0 4 -(l-(4-methoxyphenyl)m. sit _5_yl)n than the 4-methoxybenzene 106557 which will be attached to the flask with Dean-Stark mesh and reflux concentrator. Doc-125- 1312682 Amine (2.46 g, 20 mmol) and pyridine_4_formaldehyde (1.9 mL, 10 mmol) in toluene (110 mL). After 4 hours, the reaction was completed by infrared analysis and mass spectrometry. The terpene was removed via a Dean-Stark side arm via a steaming house, and the residue was dissolved in a methanol (1 mL) using decyl alcohol (20 mL) and 1,2-dimethoxy ethane (20 mL). Approximately 1% of the crude imine (approximately 1 mmol, 50 mL of methanol) was diluted. The solution was then treated with sodium carbonate (2.76 g, 20 mmol) and methyl isocyanate toluenesulfonate (T0SMIC, 2.93 g, 15 mmol) and heated in reflux for 3 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was dissolved in methylene chloride and washed with brine. The brine layer was extracted with methylene chloride and the combined organic layers were dried (MgS 〇 4) and filtered. And concentrated in a vacuum. The residue was chromatographed eluting with ethyl acetate-hexane-methanol (EtOAc: EtOAc: EtOAc (EtOAc: EtOAc) 1 〇〇 MHz, CDC 13) The signals are δ 160.039, 150.161, 141.009, 137.240, 130.839, 129.179, 127.287, 121.597, 115.106, 55.801; MS (AP/CI) 252.4 (Μ+Η)+. Preparation 81 4-(1-(4-(Benzyloxy)phenyl)-111-imidazol-5-yl) &quot;Bipyridine The title compound was prepared as described in Preparation 80, 4-benzyloxy Aniline substituted 4-methoxyaniline and gave 4-(1-(4-(benzyloxy)phenyl)-1Η-imida-5-yl) than poor' with 54% yield; with diagnostic type 13C The NMR signals were (1 〇 0 MHz, CDC13) δ 159.195, 150.132, 141.001, 137.263, 136.403, 130.892, 130.735, 129.389, 128.932, 128.521, 127.751, 127.317, 121.627, 116.078, 106557.doc -126- 1312682 70.637; MS (AP/CI) 328.4 (M+H)+. Preparation 82 4-(1-(4-Methoxyphenyl)-2-methyl-1H-imidazol-5-yl) Tetrahydrobitate biting in diisopropylamine (0.51 mL, 3.6 mmol) A solution of bromo (12 mL) was taken at -20 °C with n-butyl (2.5 EtOAc in hexane, 1.45 mL, 3.6 mmol) and the mixture was stirred for 10 min. The preparation 8 〇(4·(1_(4_methylmercaptophenyl)) was bitten (730 mg, 2. 9 mmol) in tetrahydrofuran solution and the solution was turned into dark orange. After 3 minutes, the temperature can be raised to 0 ° C. After cooling to -20 ° C, a solution of methyl iodide (0.54 mL, 8.7 mmol) in tetrahydrofuran (12 mL) is added and the solution is stirred at _2 Torr. After 30 minutes and stirring at 23 ° C for 2 hours, the solvent was removed in vacuo, the residue was diluted with brine and evaporated with ethyl acetate. The organic layer was then dried (Mgs </ RTI> 4), filtered and concentrated in vacuo. Purification by gelatin chromatography using ethyl acetate-hexane-methanol (63:32:5 to 72:18:10) to give 555 mg (72% yield) of the title compound; for the diagnostic type &quot;cnMR, the signal is ( 100 MHz, CDCI3) δ 160.144, 150.034, 149.197, 137.749, 131.265, 129.463, 128.985, 128.828, 120.849, 115.233, 55.78, 14.203; MS (AP/CI) 266.4 (Μ+Η)+. Preparation 83 4-( 2 -Ethyl-1-(4-methoxyphenyl)-1 Η-° ί 坐-5-yl) π ratio bite The title compound was prepared by the method described in Preparation 82. Ethyl moth replaces moth and produces 83% yield of 4-(2-ethyl-1-(4-methoxyphenyl)-1Η-imidazol-5-yl)pyridine·'is diagnostic&quot; The NMR signals were (100 MHz, CDCI3) δ 160.144, 150.147, 149.990, 137.786, 106557.doc • 127· 1312682 129.239, 129.037, 128.992, 121.597, 120.909, 115.181, 55.771, 21.097, 12.348; MS (AP/CI) 280.5 (M+H)+ ° Preparation 84 4-(5-(Pyridin-4-yl)-1Η-imidazol-1-yl)phenol. Preparation 81 (4-(1-(4-(benzyloxy)) Phenyl)-lH-imidazole-5-ylpyridinium, 2 g, 6.1 mmol) and anisole (13 mL, 122 mmol) in trifluoroacetic acid (50 mL) were warmed at 75 ° C for 24 hours. The solvent was removed in vacuo and the residue was purified eluted eluted elut elut elut elut elut elut elut The signals obtained by i3CNMR were (100 MHz, CDC13) δ 158.402, 149.145, 141.061, 138.018, 120.600, 129.822, 127.482, 127.370, 121.933, 116.497; MS (AP/CI) 238.3 (Μ+Η)+. Preparation 85 4-(2-Methyl-5-(pyridin-4-yl)·1Η-imidazolyl)phenol

A solution of tribrominated butterfly (1_methylene chloride, 2.1 mL, 2.1 mmol) was added dropwise to the preparation μ (4_(1_(4_曱oxyphenyl)_2_methyl_) at 〇 °C _Migui _5·base) ° in a solution of pyridine [220 mg, 〇·83 mmol) in methylene (5 mL). After 24 hours at 23 ° C (four), add an aqueous solution of sodium hydroxide (in, 15 and mix the mixture at 23 C for 1 day. Use aqueous hydrochloric acid (i... adjust the pH to 7' sub-mix the mixture) The organic layer of 'σ σ was dried (MgS04) using methylene gas/isopropyl material (4',), filtered and condensed in a vacuum. The residue was chromatographed with chloroform-methanol. To 13), the title compound of 屯化仔 to l5〇mg (72% yield); the signal obtained by diagnostic type C is (1(8)MHz, CDC13) s 159.337 106557.doc, 128-1312682 149.548, 149.302, 138.302, 131.131 , 128.760, 128.170, 127.310, 121.163, 117.237, 13.881; MS (AP/CI) 252.4 (M+H)+. Preparation 86 4-(2-ethyl-5-(pyridin-4-yl)-1H- Imidazol-1-yl)phenol The title compound was prepared using the procedure 4 as the starting material and used in the preparation of product 85. This afforded 4-(2-ethyl-5-(«»比乙-4-基)-1Η-Miso-1-yl)phenol with 70% yield; signal obtained by diagnostic 13C NMR (100 MHz, CD3OD/CDCI3) δ 158.574, 149.182, 149.002, 138.511, 130.877, 128.895, 128.20 0,127.340,121.253, 116.692, 20.656, 12.020; MS (AP/CI) 266.4 (Μ+Η)+. Example 82 2-((4-(5-(&quot;Bi-4-yl)-1Η- Imidazolyl-1-yl)phenoxy)methyl)quinoline will be prepared as 84 (4-(5-(&quot;Bite-4-yl)-1Η- tazen-1-yl), 95 mg, 0.4 mmol), a mixture of 2-chloromethylquinoline hydrogen chloride (128 mg, 0.6 mmol) and cesium carbonate (391 mg, 1.2 mmol) in dimethyl sulfoxide (2 mL) was stirred at 23 ° C for 24 hours. The mixture was diluted with ethyl acetate / n-butanol (1 mL / 5 mL), washed with brine and dried with brine (MgSO4), filtered and concentrated in vacuo. The analytical method was purified with chloroform/methanol (50:1) to give 150 mg (yield: 99% yield) of the title compound of the product (100 MHz, CDC13) δ 158.940, 157.116, 149.990, 147.836, 141.054, 137.405 , 130.989, 130.204, 129.650, 129.239, 127.953, 127.871,

127.392, 127.011, 121.627, 119.324, 116.198, 71.990; MS 106557.doc .129- 1312682 (AP/CI) 379.4 (M+H)+. Example 83 2-((4-(2•methyl-5-(acridin-4-yl)-1Η-imidazol-1-yl)phenoxy)methyl)quinine using Preparation 85 and described in the Examples The title compound was prepared by the method of 82; 88% yield; the signals obtained by diagnostic 13C NMR were (100 MHz, CDC13) δ 159.060, 157.078, 150.004, 147.836, 137.689, 137.397, 130.204, 129.934, 129.239, 128.962, 127.968, 127.871, 127.385, 127.011, 120.886, 119.354, 116.273, 71.975, 14.225; MS (AP/CI) 393.49 (Μ+Η)+. Example 84 2-((4-(2-Ethyl-5-(pyridin-4-yl)-1 Η-imidazol-1-yl)phenoxy)methyl)quinolin using Preparation 86 and described in Example 82 The title compound was prepared by the method; 92% yield; the signal obtained by diagnostic 13C NMR was (100 MHz, CDC13) δ 159.090, 157.078, 150,147, 149.930, 147.836, 137.734, 137.405, 130.211, 129.680, 129.232, 129.127, 128.970, 127.968 , 127.886, 127.392, 127.018, 120.961, 119.354, 116.243, 71.968, 21.090, 12.333; MS (AP/CI) 407.5 (M+H)+ 〇Preparation 87 N-(4-methoxyphenyl) A solution of p-nonionine (2 46 mL) in ethyl acetate (2 〇〇 mL) of p-oxoethoxyaniline (2.46 g, 20 mmol) and triethylamine (13.9 mL, 100 mm 〇l) 106557.doc -130- 1312682 g, 20 mmol) was treated with 1-propanephosphoric acid anhydride (5% in ethyl acetate, 15.1 mL, 24 mmol). After stirring for 4 hours at 23 ° C, the reaction mixture was diluted with EtOAc EtOAc. Purification by gas chromatography-methanol (40:1) afforded 4 g (yield: 88% yield) of the title compound as the title compound (1 〇〇MHz, CD30D/CDC13) δ 164.825, 157.213 , 149.758, 143.349, 130.989, 123.085, 122.068, 55.285; MS (AP/CI) 229.3 (Μ+Η)+. Preparation 88 4-(1-(4-Methoxyphenyl)_1Η-imidazole-2_ylpyridinium Preparations 87 (Ν-(4·曱oxyphenyl)isonicotinamide, ig , 4.39 mmol) dissolved in phosphorus phosphide (p〇ci3) (5 mL), followed by the addition of phosphorus pentoxide (913 mg, 4-39 mmol). The mixture was heated at 12 Torr for 4 hours. P0C13 was added in vacuo. Remove 'Aminoacetaldehyde dialdehyde (9.5 mL, 87.8 mmol) and isopropanol (10 mL)' and stir the mixture for about 16 hours at 23 ° C. Concentrate the reaction mixture in vacuo and add concentrated hydrochloric acid (36.5 %, 25 mL) Isopropanol (15 mL) solution "The reaction mixture was heated at 9 ° C for 24 hours. After cooling to 23 ° C, an aqueous solution of sodium hydroxide (1N) and aqueous sodium hydrogencarbonate was added to obtain pH = 8. The mixture was extracted with methylene gas, dried (MgSCU) and filtered and concentrated in vacuo. The residue was purified eluting with ethyl acetate/hexane/methanol (80:20:0 to 76 : 19 : 5) Purification to give 811 mg (74% yield) of the title compound; obtained by diagnostic i3c NMR 5 (1 〇〇 MHz, CDCI3) δ 160.069, 149.952, 144 142 137.853, 131.004, 129.882, 127.414, 124.977, 122.195 106557.doc -131 - 1312682 115.1 14, 55.808; MS (AP/CI) 252.4 (M+H)+ Preparation 89 4-(2-(°fcb bite The title compound was prepared by substituting Preparation 88 with Preparation 88; 86% yield; the signal obtained by diagnostic 13C NMR was obtained by the method described in Preparation 85. (100 MHz, CD3OD/CDCI3) δ 158.372, 149.145, 143.641, 138.257, 129.232, 128.985, 127.347, 125.418, 122.666, 116.505; MS (AP/CI) 238.4 (Μ+Η)+. Example 85 2-((4 -(2-(&quot;Bipyridin-4-yl)-1Η-imidazol-1-yl)phenoxy)methyl)quinoline was prepared by the method described in Example 并 and substituting Preparation 89 for Preparation 84 The title compound; 98% yield; obtained by diagnostic 13c NMR (100 MHz, CDCI3) δ 158.948, 157.108, 149.847, 147.814, 137.868, 137.420, 131.445, 130.226, 129.942, 127.968, 127.871, 127.534, 127.026, 124.954, 122.247, 119.339, 116.190, 71.968; MS (AP/CI) 379.4 (Μ+Η)+. The invention described and claimed herein is not limited to the specific examples disclosed herein. As the specific examples are intended to be illustrative of various aspects of the invention, the same specific examples are intended to be encompassed by the present invention. Within Fan 4. In fact, the various modifications of the invention, in addition to those shown and described herein, are apparent to those skilled in the art. This amendment is also intended to cover the scope of the additional patent application. 106557.doc -132-

Claims (1)

, Patent Application No. 00682&gt; 替换 Replacement of Patent Scope (February 1998) j--------, Patent Application: • *****&quot;*&quot;***** »»*_1___|丨,,,Ι,h“1 】_ m A compound's group selected from the group consisting of: 2-[_4_(4-0 ratio bite-4-yl-scraprazole_3 _ phenyloxymethyl]-carboline; 2-[4-(2-methyl- 4-acridine_4~2H-pyrazole-3-yl)-phenoxyindenyl]-喧[4 (1曱- 4 -pyridin-4-yl_1H-pyrazol-3-yl)-phenoxyindenyl]-quinoline; [4 (2 ethyl·4-tonidine) _yl-2-brazol-3-yl)-phenoxyindenyl]-quinoline; 2-[4-(1-ethyl-4-pyridine-4-yl-1H-pyrazole_3_ylbenzene Oxymethyl]quinoline; monomethyl-(2-{4-pyridine-4-yl_3_[4-(quinoline-2-ylmethoxy)phenyl]_. 嗤-1-yl} -ethyl)-amine; monomethyl-(2-{4-&quot;bipyrimidin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl; μ ° azole -1-yl}-ethyl)-amine; 1-{4-pyridin-4-yl-3_[4-(quinolin-2-ylmethoxy)phenyl]-pyrazolbyl}-propane-2 - alcohol; 1-{4-pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)phenyl]pyrazolyl}-propan-2-ol; 2- [4 - (2- different Base_4_. than k&amp;_2H_d, _3_yl)-phenoxymethyl]-quinoline; 2-[4-(4-oxaridin-4-yl-isoxazole) Phenoxymethyl]-quinoline; 2-[4-(5-acridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline; 2-[4-(2- Methyl-5-pyridine-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline; 106557-980203.doc 1312682 . 2-[4-(2-methyl-6-acridine 4-yl-pyrazolo[1,5-a]pyrimidin-7-yl)-phenoxymethyl]-quinoline; 2-[4-(2-mercapto-6-° ratio. 4-based-[1,2,4]tris-sigma and [1.5-a]af -7-yl)-phenoxyindenyl]-quinoline; 2-[4-(4-嗒耕-4 -yl-2H-carbazol-3-yl)-phenoxymethyl]-quinoline; 2-[4-(1-methyl-4-indol-4-yl-1H-indazole-3- 2-phenoxymethyl]-quinoline; 2-[4-(2-methyl-4-indol-4-yl-2H-.pyrazol-3-yl)-phenoxyindenyl] -Quino 2-[-4-(4-pyrimidin-4-yl-2indole-pyrazol-3-yl)-phenoxyindolyl]-quinoline; 2-[4-(4-嗒耕-3- 2-[4-[4-(3-methyl-isoxazol-5-yl)-2indole-pyrazole; 2-{4-[4-(3-methyl-isoxazol-5-yl)-2-indole-pyrazole -3-yl]-phenoxyindenyl}-salin; 2-{4-[2-methyl-4-(3-indenyl-isoxazol-5-yl) -2Η-pyrazol-3-yl]-phenoxyindenyl}_quinoline; 2-{4-[1-methyl-4-(3-indolyl-iso-oxazole-5-yl)- 1-Η-pyrazol-3-yl]-phenoxymethyl}-quinoline; 2-{4-[2-mercapto-5-(3-methyl-isoxazol-5-yl)-pyrimidine 4-yl]-phenoxyindenyl} -17-quineline, 2-[4-(2-°-pyridin-4-yl-2H-. Bisazo-3-yl)-phenoxyindenyl]-quinoline; 2-[4-(3-methyl-5-acridin-4-yl[1,2,4]triazol-4-yl )-phenoxyindenyl]-indole; 2-[4-(1-indolyl-4-acridin-4-yl-lH-ηpyrazol-3-yl)-phenoxyindenyl]-quin喏琳; 106557-980203.doc 1312682 - 7 - gas - 2- [4-(l-methyl-4 -D than sigma-4 -yl-1Η - 0 ratio. sit-3-yl)-phenoxy Hydroquinone hydrogenation; 6-fluoro-2-[4-(l-methyl-4-acridin-4-yl-1H-.pyrazol-3-yl)-phenoxyhydrazine Hydrocarbyl hydrogen; 2-[2-fluoro-4-(4-acridin-4-yl-1H-»pyrazol-3-yl)-phenoxyindolyl]-quinoline; -[2-Fluoro-4-(1-methyl-4-acridin-4-yl-1Η-°boxazol-3-yl)-phenoxyindolyl]-quinoline; 2-[2,3 -difluoro-4-(1-methyl-4-acridin-4-yl-1Η-pyrazol-3-yl)-phenoxymethyl]-quinoline; 2-[3- gas-4- (4 -0 σ 定 -4 -yl -1 Η -π ratio 0 -3 -yl)-phenoxymethyl]-喧 Lin; 2-[4-(5-pyridin-4-yl-1Η- Pyrazol-4-yl)-phenoxymethyl]-quinoline; 2-[4-(1-methyl-5-°pyridine-4-yl-1Η-0 to 0--4-yl )-Benzylmethylmethyl--indole; 2-[4-(1-methyl-3-0-butoxy-4-yl-1Η-D ratio σ--4-yl)- Phenoxymethyl]-喧' lin; 2-mercapto-1-{4-pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyridyl. -1 -yl}-propan-2-propionate, 2-methyl-1-{4-pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl]- Pyrazole-1-yl}-propan-2-ol; (R)-l-{4-acridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl] Bis-l-yl}-propan-2-ol; 106557-980203.doc 1312682 (S)-l-{4-Acridine-4-yl-3-[4-(quinolin-2-ylindole Benzyl-l-yl]-pyrazole-l-yl}-propan-2-ol; 2-[4-(1-isopropyl-4-pyridin-4-yl-111-carbazole-3 -yl)-phenoxyindenyl]-salin; 2-[4-(1-isobutyl-4-acridin-4-yl-1H-indazol-3-yl)-phenoxyfluorenyl ]- 喧琳; 2-[4-(1-indolyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxyindolyl]-[1.8]cridine; 2-{ 2-[4-(4 - ° ratio. definite -4 -yl-2 Η -D is more than α -3 -yl)-phenyl]-ethyl}-喧琳, 2-{2-[4-( 1-mercapto-4-pyridin-4-yl-1Η-pyrazol-3-yl)-phenyl]-ethyl}-quinoline; 2-{4-[4-(2-chloro-acridine- 4-yl)-1Η-°bazol-3-yl]-phenoxyindenyl}-quinolin; 2-{4-[4-(2-chloropyridin-4-yl)-1-methyl -1Η-oxazol-3-yl]-phenoxymethyl}-quinoline; 2-{4-[1-mercapto-4-(2-indolyl-acridin-4-yl)-1Η- Σβoxazol-3-yl]-phenoxymethyl}-嗤·; dimethyl-(4-{1-methyl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-1Η-. than 〇 4 - 丨-α ratio定-2-yl)-amine, 2-[4-(5-acridin-4-ylpyrazol-1-yl)-phenoxymethyl]-quinoline; 2-[4-(3- Methyl-5-acridin-4-yl-pyrazol-1-yl)-phenoxyindenyl]-quinoline; 2-[2-chloro-4-(4-acridin-4-yl-1H -pyrid-3-yl)-phenoxyindenyl], quinine 106557-980203.doc -4- 1312682 2-[2-gas-4-(1-mercapto-4-acridin-4-yl- 1H-pyrazol-3-yl)-phenoxyindenyl]-indole; 2-[4-(4-.pyridin-4-yl-4H-[1,2,4]triazole-3- 2-phenoxymethyl]-quinolin; 2-[4-(5-acridin-4-yl-[1,2,4]triazol-1-yl)-phenoxyindenyl]- Quinoline; 2-[4-(3-indolyl-5-pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxyindolyl]-indolyl, 2-[ 4-(2-Acridine-4-yl-2H-[1,2,4]triazol-3-yl)-phenoxymethyl]-quinolin; 2-[4-(5-fluorenyl- 2-pyridin-4-yl-2H-[1,2,4]triazol-3-yl)-phenoxymethyl]-quinoline; 8-methoxy-2-[4-(1-曱) 4-[4-(1-methyl-4-acridin-4) 4-pyrimidin-4-yl-1Η-°boxazol-3-yl)-phenoxymethyl]-indole -yl-1H-pyrazol-3-yl)-phenoxy Mercapto]-pyridinium [l,2-a]° dense sigma-4-one; 2-[4-(1-methyl-4-acridin-4-yl-1Η-carbazole-3- Benzyloxymethyl]-quinoline; 2-[3-fluoro-4-(1-methyl-4-pyridin-4-yl-11^-pyrazol-3-yl)-phenoxy 4-chloro-2-[4-(1-methyl-4-pyridin-4-yl-1Η-pyrazol-3-yl)-phenoxyindenyl]-quineline 4-methoxy-2-[4-(1-indolyl-4-pyridin-4-yl-111-. Bisazo-3-yl)-phenoxymethyl]-indole; 106557-980203.doc 1312682 dimethyl-{2-[4-(l-fluorenyl-4-pyridin-4-yl-1H- 2-oxazol-3-yl)-phenoxymethyl]-salt-4--4-yl}-amine; 2-[4-(1-mercapto-4-acridin-4-yl-lH-α ratio Zyrid-3-yl)-benzyloxy]-quinoline-di-succinic acid; 2-((4-(5-(pyridin-4-yl)oxazol-4-yl)phenoxy)methyl) Quinoline; 2-((4-(2-mercapto-5-(acridin-4-yl)oxazol-4-yl)phenoxy)indolyl)quinine; 2-((4-(3) - mercapto-4-(acridin-4-yl)-1 -oxazol-5-yl)phenoxy)indolyl) 2-((4-(1,3-dimethyl-4) -(pyridin-4-yl)-1Η-oxazol-5-yl)phenoxy)methyl)quinoline; 2-((4-( 1,5-dimethyl-4-(acridin-4) -yl)-1Η-.pyrazol-3-yl)phenoxy)indolyl) 2-(1-(4-(1-methyl-4-(pyridyl)-4-yl)-1Η- Oxazol-3-yl)phenoxy)ethyl)indole; 2-((4-(5-(acridin-4-yl)-1,2,3-triazol-4-yl)phenoxy Quino) quinoline; 2-((4-(2-methyl-5-(pyridin-4-yl)-2Η-1,2,3-triazol-4-yl)phenoxy) oxime 2-((4-(3-methyl-5-(pyridin-4-yl)-3Η-1,2,3- Triazol-4-yl)phenoxy)nonyl)quinoline; 2-((4-(1-(.pyridin-4-yl)-1Η-imidazol-2-yl)phenoxy)indolyl Quinoline; 2-((4-(5-(acridin-4-yl)-1Η-imidazol-1-yl)phenoxy)indolyl)quinoline; 2-((4-(2-) 5-((pyridin-4-yl)-1Η-imidazol-1-yl)phenoxy)indolyl) hydroxyquine; 106557-980203.doc 1312682 2-((4-(2 quinoline; -ethyl-5-(pyridine-4-yl)_1H-imidazol-1-yl)phenoxy)indolyl) and pharmaceutically acceptable salts thereof. 2. A compound as claimed in claim 1 which is a township methyl-4W-prepared 1H-bisazolyl)phenoxyindenyl]-quinoline or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is a statin of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus. 4. The compound of claim 1, which is 2-[4_(2·Ψ基_4_terminal 4_yl 2Η·biazole-3-yl)-phenoxymethyl]-quinoline or a pharmaceutical thereof Acceptable cockroaches. 5. As requested by the compound, it is 2 cases of 2_ethyl such as biting ice base 嗤 口 嗤 嗤 基 基 基 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其Compound, complex A2 f4n 7 | present, horse 2-[4·(1-ethyl_4.pyridine·4·*_ιη_pyrazol-3-yl)-phenoxymethyl], or its Pharmaceutically acceptable salts. 7' A compound selected from the group consisting of: 孓{4小^定-4_基_2_(2,2,2-trifluoroethyl)-2-heart 嗤oxymethyl} - quinoline; ” 2/4+μ_4_yl is small (2,2,2-tri-Iethylhumyl]-phenoxymethyl}-quinolin; fluoro-ethyl)-1Η-. Bizoazole-3-both 'ethyl}-111-° ratio. Sit 3--3-3-fluoro-4-[4-° ratio -4-yl-;[·(2,2,2-triyl]-phenoxymethyl}-喧琳; 2- {3-Fluoro-4-[4-pyridin-4-yl_1_(2,2,2-triyl)-phenoxyindolyl}-quinoline; I06557-980203.doc 1312682 2-{4 -[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1 Η-pyrazol-3-yl]-phenoxymethyl}-quinoxaline; A pharmaceutically acceptable salt. 8. A pharmaceutical composition comprising a compound of claim 1. 106557-980203.doc